Introduction
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.
Vaccine technology specific considerations
The safety assessment of live attenuated and replicating viral vector vaccines in HIV infected subjects should follow a scheme reflecting the benefit risk ratio at time of assessment, the controlled/uncontrolled status of HIV infection and may vary with the target population.
- Define the safety endpoints for Phase 1
- Safety endpoints for Phase 1 defined
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.
- Safety endpoint approved
- Safety endpoint approved
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.
- Analyse FIH/Phase 1 safety data
- Safety profile of selected doses or regimen of FIH/Phase 1 supports subsequent Phase 2a
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) should indicate an acceptable reactogenicity profile of the different vaccine doses which are being considered for Phase 2a studies. No safety concerns precluding further clinical development should have been identified.
TB vaccine target population 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.
- Analyse all safety data from Phase 2a
- Safety profile of the dose selected for Phase 2b acceptable
The review of all cumulative reactogenicity and safety data across the different studies (Phases 1 and 2a, pre-proof of concept study whenever carried out) should 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 should be no evidence of a clinically meaningful safety signal.
If the immunisation schedule consists of 2 or 3 vaccine administrations, there should be no evidence of an unacceptable dose-related increase in reactogenicity.
TB vaccine target population 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 should 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 should support the dose and timing of vaccine administration related to the antibiotic treatment.
- 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
- Safety profile acceptable in target population
- RMP for Phase 3 drafted and active surveillance updated
At stage G, the review of Phase 2b data should 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 should indicate 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.
A plan to assess vaccine safety in HIV infected individuals is prepared, if it has not already been conducted (for example, for subunit vaccines).
TB vaccine target population considerations
Neonate/infant vaccine: Safety data on concomitant administration with EPI vaccines should be acceptable.
- Evaluate pre-licensure safety against TPP
- Assess the ratio of benefit-risk
- Draft a post-marketing RMP, including evaluation in specific target studies (i.e. HIV infected individuals)
- Pre-licensure safety is acceptable and meets TPP
- Favourable benefit-risk assessed
- Post-marketing RMP is drafted, and includes post_marketing safety evaluation study and specific target studies
The review of Phase 3 safety data evaluates further the profile of common and less common reactions induced by vaccination. The pooled analysis of safety data should support an acceptable safety profile in the target population, as per TPP. When available, preliminary data in HIV-infected individuals should not raise a safety concern in this population.
- Finalise post-marketing Risk Management Plan (RMP), including evaluation of safety in specific target populations (for example HIV+)
- Post-marketing RMP finalised and approved
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.