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. Safety concerns have not been identified.

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 (Phase1 and 2a, pre-proof of concept study whenever carried out) indicate that the vaccine formulation, dose and vaccination schedule selected for Phase2b 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.

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 0.01% 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 may be modified in case of occurrence of any unexpected event during the Phase 2b trial.

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

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

At stage H, the review of Phase 3 data confirm the profile of common and less common reactions. The pooled analysis of safety data support an acceptable safety profile in the target population which meets the TPP.

Preliminary data in HIV-infected individuals do not indicate a safety concern in this population and this should be confirmed in a Phase 3 trial.

A post-marketing safety study should address any unexpected event which would have occurred during pre-licensure clinical trials.