Function

The aim is to monitor and evaluate the efficacy of the candidate vaccine to conclusively demonstrate that immunisation induces protection against TB disease. Prevention of active TB disease in a general, healthy population remains the primary focus of vaccine development. This assessment will need large sample size and long duration of follow-up. Given the limitations of immunogenicity data from Phase 2 studies to predict efficacy, pre-proof of concept studies using other read-outs (e.g. prevention of infection) might be considered before long and highly resource-consuming efficacy Phase 3 trials are conducted.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • Define endpoints for pre-POC study (if warranted) together with endpoints for efficacy in a Phase 2b
CRITERIA REQUIRED
  • Endpoints for pre-POC or first efficacy trial defined
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Guidance

Pre-proof of concept trials are considered in subjects who are at high risk of an outcome of interest such as Mtb infection. Although Mtb infection would not be seen as a licensable clinical endpoint by a stringent regulatory authority, prevention of infection (POI) would indicate biological activity of vaccine-induced immune response which could be seen as a clinically relevant biological signal and potential indicator of vaccine efficacy.

Another pre-POC pathway is represented by prevention of recurrence (POR) trials in patients recently treated for TB and cured, as these individuals are at high risk of recurrence (by a combination of endogenous relapse and exogenous reinfection).

The study design for Phase 2b will reflect the statistical hypothesis: usually superior efficacy over either placebo or benchmark vaccine (e.g. BCG). The magnitude of superiority should reflect the expected improvement in public health outcomes. The preferred primary endpoint for Phase 2b should be bacteriologically confirmed i.e., culture and/or GeneXpert+) cases of TB disease using standardised case definition (WHO definitions of TB 2014). Culture confirmation or WHO approved rapid diagnostic (WRD) such as Gene Xpert technology based test is required rather than the less sensitive and less specific smear microscopy.

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • If applicable, analyse pre-POC data
  • Confirm efficacy endpoints of Phase 2b
CRITERIA REQUIRED
  • Whenever available, pre-POC data are supportive
  • Efficacy endpoints for Phase 2b confirmed
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Guidance

If a POI study has been conducted, and POI study data show a statistically significant reduction in the defined primary endpoint and meet the Go criteria, one could prepare for a Phase 2b/3 POD trial (depending on magnitude and significance of the result and on an acceptable safety/tolerability profile). However, the absence of a vaccine’s ability to prevent infection does not necessarily mean absence of efficacy in preventing disease as the immune mechanisms by which a vaccine might prevent infection and disease could be different. Also, demonstration of POI does not guarantee POD since approximately 90% of infected individuals never progress to active TB even in the absence of effective vaccination. To know that a vaccine will protect people from active TB and avert cases and deaths, it must be demonstrated that a vaccine candidate shown to prevent infection does so in individuals who, without vaccination, would have developed active TB. A convincing robust data package demonstrating pre-clinical and clinical safety, immunogenicity, and pre-POC human data will likely need to be assembled to proceed to Phase 2b. Robust protection data in a relevant animal model might be seen as adequate support even in the absence of pre-POC human efficacy data, although to date, none of the animal models has been demonstrated to be predictive for vaccine protection in humans.

Another approach to obtaining proof of concept is to conduct a Phase 2b POD trial in a high risk of disease population (to keep size and cost of the trial as low as possible). This could be a QFT-positive adult population, as one example, if the vaccine candidate is hypothesised to prevent disease post-infection.

Primary and secondary endpoints of protective efficacy against TB disease in line with WHO definition are agreed/ confirmed for the Phase 2b trial.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Establish clinical Proof of Concept (POC) efficacy
CRITERIA REQUIRED
  • Evidence of efficacy from Phase 2b or interim analysis consistent with minimal TPP criteria (based on predefined criteria)
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Guidance

Analysis of the data from the Phase 2b trial demonstrates protective efficacy against the primary case definition endpoint that is greater or equal to the minimum predefined efficacy criterion as set in the TPP, allowing for extending efficacy evaluation in a Phase 3 trial.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Evaluate clinical efficacy against TPP
  • Establish plan for phase 3 extension
  • Draft a post-marketing evaluation plan for vaccine effectiveness
CRITERIA REQUIRED
  • Protective efficacy meets TPP
  • Plan for phase 3 extension established if needed
  • Draft post-marketing effectiveness evaluation plan (Phase 4, etc.) available
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Guidance

Analysis of the data from the Phase 3 trial confirmed protective efficacy against the primary case definition endpoint greater or equal to the minimum predefined efficacy as set in the TPP in the target population for licensure.
Post-marketing studies to confirm vaccine effectiveness should be planned to confirm effectiveness, duration of protection and the need for booster immunisations, as well as effectiveness in specific sub-populations.