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

Thanks for your attention!