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.
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.
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.
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.
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.
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).
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.