Function

The aim is to monitor and evaluate the safety of the product through clinical studies as described in the clinical development plan. Standardised definitions of adverse events following immunisation and data collection should be used across all clinical trials (from Phase 1 to Phase 3) to allow pooled analysis of safety data. Due to the co-occurrence of Mtb infection and HIV infection in many TB-endemic regions and the severe outcome of Mtb infection in HIV-infected individuals, the safety of new TB vaccines will need to be assessed in both, HIV-uninfected and HIV-infected, individuals.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Define the safety endpoints for Phase 1
CRITERIA REQUIRED
  • Safety endpoints for Phase 1 defined
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Guidance

The assessment of safety is the primary objective of Phase 1 and 1b studies. An important aspect at this stage is therefore to define the safety endpoints for these studies.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Safety endpoint approved
CRITERIA REQUIRED
  • Safety endpoint approved
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Guidance

The local and systemic adverse events to be monitored during the Phase 1 and 1b studies are reviewed and approved.

In case of a live attenuated vaccine, a plan to assess vaccine shedding is prepared.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • Analyse FIH/Phase 1 safety data
CRITERIA REQUIRED
  • Safety profile of selected doses or regimen of FIH/Phase 1 supports subsequent Phase 2a
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Guidance

The safety data of the Phase I study and Phase 1b in the target population (eg healthy neonates, or Mtb non-infected and/ or infected adults from endemic regions) indicate an acceptable reactogenicity profile of the different vaccine doses which are being considered for Phase 2a studies. No safety concerns have been identified.

Target-specific considerations

Adolescent/ adult vaccine: Safety data in both QTF- and QTF+ adults are required.

Neonate/ infant vaccine: Develop a plan to assess safety in HIV exposed, as well as unexposed neonates and infants. For a neonatal BCG-replacement vaccine candidate, plan to evaluate safety in comparison to BCG in HIV exposed neonates.

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • Analyse all safety data from Phase 2a
CRITERIA REQUIRED
  • Safety profile of the dose selected for Phase 2b acceptable
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Guidance

The review of all cumulative reactogenicity and safety data across the different studies (Phase 1 and 2a, pre-proof of concept study whenever carried out) indicate that the vaccine formulation, dose and vaccination schedule selected for Phase 2b study has an acceptable safety profile in terms of nature,severity and duration of adverse events. There is no evidence of a clinically meaningful safety signal.

If the immunisation schedule consists of 2 or 3 vaccine administrations, there is no evidence of an unacceptable dose-related increase in reactogenicity.    

Target-specific considerations

Adolescent/adult vaccine: Phase 2 studies confirm that safety is acceptable in both QTF- and QTF+ adults.

Neonate/infant vaccine: Safety/ tolerability data from Phase 1b and 2 studies compared to BCG appear acceptable. In the hypothesis that a better safety profile is the rationale of the improvement upon current BCG vaccination, Phase 1b and 2 data should support this hypothesis.

Therapeutic vaccine: Phase 2 safety data support the dose and timing of vaccine administration related to the antibiotic treatment.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Analyse all safety data from earlier trials, including Phase 2b
  • Draft Risk Management Plan (RMP) for Phase 3 and update active surveillance if needed/ justified
CRITERIA REQUIRED
  • Safety profile acceptable in target population
  • RMP drafted and active surveillance updated
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Guidance

At stage G, the review of Phase 2b data confirm the profile of common reactions in terms of nature, severity and duration and indicate that there are no unexpected, less common (frequency of 0.1% to 1 %) adverse events. Altogether,experience from all studies indicates an acceptable safety profile in the target population. The active monitoring of adverse events during Phase 3 maybe modified in case of occurrence of any unexpected event during the Phase 2b trial.

A plan to assess vaccine safety in HIV infected individuals is prepared, if it has not already been conducted (for example, for subunit vaccines).

Target-specific considerations

Neonate/ infant vaccine: Safety data on concomitant administration with EPI vaccines is acceptable.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Evaluate safety against TPP
  • Draft a post-marketing RMP, including evaluation in specific target studies (i.e. HIV infected individuals)
CRITERIA REQUIRED
  • Pre-licensure safety is acceptable and meets TPP, allow a favourable benefit-risk assessment
  • Post-marketing RMP is updated and includes post_marketing safety evaluation study and specific target studies
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Guidance

During the Phase 3 trial biospecimens have been collected. The investigational plan to identify a CoPshould be developed based on the analysis of Phase 3 immunogenicity andefficacy data.

Stage 
I
Register vaccine with relevant Regulatory Authorities
Gate 
I
Obtain MA and Progress to launch
Main Activities
  • Finalise post-marketing Risk Management Plan (RMP), including evaluation of safety in specific target populations (HIV+)
CRITERIA REQUIRED
  • Post-marketing RMP finalised and approved
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Guidance

Phase 4 safety study should be prepared to address any unexpected event of specific interest which would have occurred during pre-licensure clinical trials and to assess any adverse event that was too rare to be observed in clinical trials.

Phase 4 safety studies should be also be prepared to assess or confirm the safety profile in specific populations that were not fully evaluated in pre-licensure trials e.g. HIV infected individuals.

Stage 
J
Launch
Gate 
J
Implement vaccination programs
Main Activities
  • Execute pharmacovigilance plan in phase 4 studies
CRITERIA REQUIRED
  • Phase 4 studies initiated
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Guidance

Phase 4 safety studies are initiated and performed as planned.

Stage 
J
Launch
Gate 
J
Implement vaccination programs
Main Activities
  • Evaluate vaccine effectiveness in phase 4 studies
  • Conduct additional co-administration studies
CRITERIA REQUIRED
  • Phase 4 studies initiated
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Guidance

Phase 4 studies to determine vaccine effectiveness are initiated and carried out as planned.