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
Due to possible dissemination of live bacteria, there have been concerns with using live attenuated vaccines, such as BCG, in PLWH, particularly those not on antiretroviral therapy (ART). Safety data from PLWH should be available for all TB vaccines, including live attenuated vaccines. The safety assessment of live attenuated and replicating viral vector vaccines in PLWH may be evaluated in Phase 2, Phase 3 and post-licensure trials. The inclusion of HIV infected subjects in early phase and licensure trials should depend on CD4 count (≥ 100 cells/mm3) or viral load (HIV RNA <200 copies/mL) and a positive risk-benefit ratio and if a positive safety signal in PLWH will support further development of the vaccine candidate (Miner et al., 2022).
- 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.
- Review and approve local and systemic adverse events to be monitored during the Phase 1 studies
- Safety endpoint approved
The local and systemica dverse events to be monitored during the Phase 1a 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 for target population and dose relevant for Phase 2a
- Safety profile of selected doses or regimen of FIH/Phase 1 supports subsequent Phase 2a
The safety data of the Phase 1a study and Phase 1b in the target population (e.g. healthy neonates, or Mtb non-exposed and/or exposed 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 vaccinetarget population considerations
Adolescent/adultvaccine: Safety data in both IGRA-negative and IGRA-positive 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. Similarly, an infant booster vaccine should be tested in comparison to a BCG prime alone.
- Analyse all safety data from Phase 2a and combine with all data from earlier studies
- 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) should indicate that the vaccine formulation, dose and vaccination schedule selected for Phase 2b study have an acceptable safety profile in terms of nature, severity and duration of adverse events. There should be no evidence of a clinically significant 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 targetpopulation considerations
Adolescent/adultvaccine: Phase 2 studies confirm that safety is acceptable in both IGRA- and IGRA+ adults.
Neonate/infant vaccine: Safety/tolerability data from Phase 1b and 2 studies compared to BCG should appear acceptable. Assuming a better safety profile is the rationale of the improvement compared to current BCG vaccination, Phase 1b and 2 data should support this hypothesis.
- 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
- Draft plan to assess safety in priority populations.
- Consider safety in case of concomitant administration of other vaccines
- Safety profile acceptable in target population
- RMP for Phase 3 drafted and active surveillance updated
- Plan drafted for safety in priority populations
- Plan drafted for safety upon concomitant administration of other vaccines (if considered relevant)
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 and other priority populations such as pregnant individuals or individuals who are breastfeeding is prepared, if it has not already been conducted.
TB vaccine target population considerations
Neonate/infant vaccine: Safety data on concomitant administration with EPI vaccines should be acceptable.
Adolescents/adults: Safety data on concomitant administration of other vaccines (such as HPV, malaria) should be considered.
- Evaluate all available data against TPP
- Assess the ratio of benefit-risk
- Draft a post-licensure RMP, including evaluation in specific priority populations (i.e. HIV infected individuals)
- Pre-licensure safety is acceptable and meets TPP
- Post-licensure RMP is drafted, and includes post-licensure safety evaluation study for target population and priority population
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 anacceptable 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 priority populations (for example PLWH)
- Phase 4 safety study drafted
- Post-licensure RMP finalised and approved
A Phase 4 safety study should be prepared to address any unexpected event of special interest identified during pre-licensure clinical trials and to assess the presence of any adverse event that was too rare to be observed in pre-licensure clinical trials.
Phase 4 safety studies should also be prepared to assess or confirm the safety profile in relevant specific populations that were not fully evaluated in pre-licensure trials e.g. HIV infected individuals or pregnant and breastfeeding individuals.