L8: Vaccine Trials Phase III

A set of vocabulary flashcards covering phases of vaccine clinical trials, study designs, non-inferiority statistical benchmarks, and pandemic acceleration frameworks.

Phase 1 Vaccine Trial

An initial clinical trial conducted in 20 to 100 healthy volunteers over 1 to 2 years to evaluate safety, tolerance, and preliminary immunogenicity.

Phase 2 Vaccine Trial

A clinical trial conducted in several hundred healthy volunteers to determine the optimal dose, formulation, and vaccination schedule while continuing safety evaluations.

Phase 3 Vaccine Program

A large-scale: 3,000 to 10,000+ participants in the target population (infants, children, older adults, pregnant)

Assess protective efficacy, uncommon side effects, manufacturing consistency (batch to batch variation), administration w other vax, laboratory correlates of protection

Phase 4 Studies

Post-licensure studies conducted to evaluate real-world effectiveness, rare side effects

How long does a phase 3 trial last & cost

~1 to 4 years

May be > $1 billion USD

Phase 3 trial inclusion population

Subjects in target population

Incl. Infants, children, older adults, pregnant mothers

Requirements for undertaking phase 3 trial (5)

• Evidence of safety and indications of potential success

• Positive discussion with regulator(s) about study design

• Sufficient funding to undertake study

• Viable market if successful

• Ability to successfully complete study

Design of Phase 3 trials

• Generally double-blind or observer blinded randomised controlled trials

• Design will depend on availability and recommendations of current vaccines and disease epidemiology

– ethics of use of placebo vaccination vs licensed comparator e.g. influenza in the elderly

– feasibility of sufficient cases for rare infections e.g. meningococcal disease

3 Phase 3 trial designs

1) Absolute vaccine efficacy

 placebo-controlled trial with infection / disease endpoint e.g. RSV or COVID-19 trials

2) Relative vaccine effectiveness

 compare the relative risk of infection in study vaccine vs comparator vaccine e.g influenza

3) Comparative immunogenicity

 used for combination vaccines to demonstrate equivalence to separate licensed vaccines

 Pertussis combination vaccines

Phase 3 trial designs:

1) Placebo controlled Phase 3 vaccine trials (absolute vaccine efficacy)

• Most common design for novel vaccines where no licensed comparators exist and correlates of protections unknown for the population

• Calculate absolute vaccine efficacy

• Uses a placebo or unrelated licensed vaccine (especially in children)

• Duration driven by overall number of events occurring to drive interim analysis and desired or expected efficacy

• Sample size for efficacy estimate also provides confidence in detecting uncommon adverse events

• Usually multi-centre, international trials at hospitals, trials centres & GPs

Phase 3 trial designs:

1) Absolute vaccine efficacy: how to calculate it

Vaccine Efficacy = 1- (Infection rate in vaccinated / infection rates in placebo recipients)

Examples of absolute vaccine efficacy phase 3 trials

Maternal bivalent RSV vax

COVID-19 vax

Phase 3 trial designs:

2) Relative Vaccine Efficacy Trials

Compared study vaccine to active licensed comparator vaccine

• e.g. higher valency, higher-dose or adjuvanted vaccines expected to have better efficacy than the existing vaccine

• compare the relative risk of infection in the new compared to existing vaccine

• Requires a high disease incidence and the licensed comparator to not have high efficacy against circulating disease

• e.g. seasonal influenza vaccine in older adults

• Sample sizes are generally larger

• Can use cluster randomised control trials

• Not feasible for many diseases especially for severe outcomes such as hospitalisation

Phase 3 trial designs:

2) Relative Vaccine Efficacy Trials example

High-dose (HD) vs Standard dose (SD) Influenza vaccine in older adults ≥65 years

Phase 3 trial designs:

3) Comparative immunogenicity

Used for combination vaccines to demonstrate equivalence to separate licensed vaccines

• Used if disease incidence is too low for placebo- controlled trial and correlate of protection is known or current vaccines are well established and are effective

• Relies on using standardised laboratory assays

• Need to show new vaccine is non-inferior to licensed comparator

• Also used to demonstrate consistency of batch to batch manufacturing

• Sample size more dependent of sufficient safety dossier

• Often have a number of similar studies in different populations submitted to regulators

Phase 3 trial designs:

3) Comparative immunogenicity - definition of inferiority

The lower bound of 2-sided 95% CI of rate of seroprotection or seroresponse is > -10%

The lower bound of the 2-sided 95% CI for IgG GMC / GMT ratio to be > 0.5

Phase 3 trial designs:

3) Comparative immunogenicity- example

• Pertussis combination vaccines

• Commonly used for combination vaccines (e.g. pertussis 6 in1 vaccines) and multivalent vaccines (e.g. pneumococcal and meningococcal conjugate vaccines

Risks of Phase 3 trials

 Disease incidence is overestimated in trial population

 Timing of vaccination related to peak disease incidence

 Wrong population selected for trial (inclusion / exclusion criteria)

 Wrong trial design or endpoint selected

 Trial is too complex for patients or for sites to undertake

 Testing for trial endpoint is not undertaken systematically

 Mechanism of protection is not understood & vaccine ineffective

 Safety issue identified

 Trial takes too long or competitor vaccine introduced

 Insufficient funding to complete trial

 Vaccine not cost-effective

What is something that is important in phase 3 trials

Multiple endpoints