general considerations for clinical trials of vaccines ming-hsiao chan, md,mph researcher/team...
TRANSCRIPT
General considerations for clinical trials of
vaccines
Ming-Hsiao Chan, MD,MPHResearcher/Team Leader, Division of Clinical Sciences,Center for Drug Evaluation, Taiwan
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.
Introduction References: 1.國內法規
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
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.
Introduction 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
Safety is always primary
CDE’s primary objectives in reviewing an IND are to assure the safety and rights of subjects.
Outlines1. Background, rationale and expected value 2. Assure rights of subjects 3. Study population4. Inclusion and exclusion criteria 5. Dose, route of administration, and
vaccination schedule 6. Safety evaluations 7. Concomitant medication8. Efficacy endpoints and design of clinical
trial9. Other studies (Lot-to-lot consistency
study)
Background, rationale and expected value
Background Mechanism Epidemiology of target disease Licensed vaccine available? Unmet medical need Prognosis and clinical presentation of
target disease
Background, rationale and expected value
Rationale Preclinical studies
a. Toxicity and safety testing b. Potency and immunogenicity
Early phase clinical studies
Background, rationale and expected value Rationale
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)
Background, rationale and expected value
Rationale 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
Background, rationale and expected value
Rationale Before phase I studies: a. Appropriate animal challenging
model b. Other approaches providing proof
of concept
Background, rationale and expected value
Expected value Plans for development of the candidate v
accine and clarify requirements for carrying out clinical trials
Expected clinical benefits of the candidate vaccine
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
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
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
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
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
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 prematurit
y) f. Allergic history g. Recent vaccinations
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
Dose, route of administration, and vaccination schedule 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 immunosupp
ressed and haemodialysis patients)
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
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
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)
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.
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
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)
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
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
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
Concomitant medication Less restriction, in general no concern regarding dr
ug interaction Usually restrict the use of immune modifying drugs
(e.g. systemic steroids, cytotoxic drugs) Exclude the subjects administered with blood prod
ucts or immunoglobulins recently Should have instructions for concomitant use of ot
her vaccines All concomitant medication use during the study s
hould be recorded
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)
Efficacy endpoints and design of clinical trial Outcome measurement:
Vaccine efficacy: The reduction of chance of developing diseas
e 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
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.
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.
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)
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
Efficacy endpoints and design of clinical trial
Surrogate endpoints Feasibility Validity Justify the use of surrogate endpoi
nt
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
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
Other studies (Lot-to-lot consistency study) Example: Seasonal influenza inactivated va
ccines 3 consecutively manufactured final formulated
bulk lots of vaccine HI antibody assay Ratio of GMTs for each viral strain contained in t
he three vaccine lots as the primary endpoint A pair-wise comparison The two-sided 95% CI on the GMT ratio: 0.6-1.5