Function

The main objective is to build a safety profile of the vaccine candidate through a series of appropriate studies in animal and in-vitro systems. In addition to specific assays to measure toxicity, early pre-clinical studies aimed at evaluating immunogenicity and/ or efficacy can be used as an additional data source for the safety profile of the vaccine candidate. Dose-ranging studies could be included to provide early safety data on higher doses than are generally used for immunogenicity or efficacy. Specific safety studies applicable to live attenuated whole cell vaccines are required and these will include high dose challenge of immunocompromised mice in addition to the tests specified in the BCG vaccine monograph (European Pharmacopoeia - European Pharmacopoeia. Strasbourg, Cedex, France: Directorate for the Quality of Medicines of the Council of Europe (EDQM). BCG vaccine, freeze-dried. 01/2012:0163, 895-896 (2012).). Formal safety and toxicity studies will be required at Stage D and beyond and will be reviewed by the appropriate regulatory authority.

Stage 
A
Perform discovery, safety, immunogenicity and efficacy evaluation in initial animal model
Gate 
A
Progress to proof of concept (POC) studies in animals
Main Activities
  • Identify in vitro and in vivo models to test for safety
  • Test preclinical safety elements relevant to candidate
CRITERIA REQUIRED
  • Safety tests identified
  • Safety evaluated; no evidence to suggest lack of safety
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Guidance

Safety testing at this Stage should first demonstrate that the vaccine material is suitable for use in animals. For example, protein components of protein/ adjuvant vaccines should be tested for and contain minimal levels of endotoxin, ensuring both that the candidate is safe for use in animals and that interpretation of immunogenicity and/ or efficacy data is not confounded by the presence of  innate stimuli. Further evaluations of safety at this Stage are generally observational, and can be included in immunogenicity and efficacy studies. These should reveal an absence of safety signals such as excessive local inflammation at the site of injection or indications of anaphylaxis with repeated inoculations. Safety characteristics specific for live attenuated whole cell vaccines (strains of Mycobacterium tuberculosis (Mtb)or modified BCG) are described in Walker et al., 2010, and are aimed at demonstrating safety better than BCG, for example in the immunocompromised SCID mouse model.

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Main Activities
  • Expand testing to confirm the general safety attributes of the vaccine candidate(s)
CRITERIA REQUIRED
  • Evidence of safety properties in one or more in vitro and / or in vivo models, confirming and expanding on tests performed in Stage A
  • Where relevant, safety in immunocompetent and immunocompromised animals demonstrated being as safe or safer than BCG
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Guidance

As pre-clinical testing of immunogenicity or efficacy continues in stage B, safety characteristics should be documented to add to the safety profile of the candidate. Additional studies may be conducted to confirm and expand the safety data package for specific product targets or functions. Examples might include an evaluation of the tolerability to different doses of the vaccine or tests to investigate shedding of live viruses or bacteria. Safety should be confirmed if there are any changes to/ optimisation of the vaccine candidate (for example, removing the resistance marker from an attenuated strain of Mtb.)

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Design pre-clinical safety and toxicology studies as required by regulatory guidelines
CRITERIA REQUIRED
  • Synopsis protocols for safety and toxicology studies prepared as relevant for the vaccine
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Guidance

Synopsis protocols should be prepared for any safety and toxicity studies required by the relevant National Regulatory Authorities (NRAs). At minimum, this generally includes a local tolerance and repeat-dose toxicity study conducted under Good Laboratory Practices (GLP). However, additional studies may be required depending on the vaccine candidate. For example, genotoxicity and carcinogenicity studies may be required for novel vaccine adjuvants. Early consultation with NRAs is recommended to ensure the proposed studies meet their expectations.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Perform toxicology studies using DP from GMP run (or equivalent)
  • Perform safety studies such as bio-distribution, persistence and for Genetically Modified Organism (GMO) requirements, as relevant for the vaccine
CRITERIA REQUIRED
  • Safety and toxicology profile of the DP acceptable
  • Bio distribution, persistence and GMO requirements met, as relevant
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Guidance

Relevant safety and toxicity studies should be performed only once the manufacturing process has been locked and GMP-quality material is available. At a minimum, Drug Product should be evaluated at the highest intended clinical dose, in an “N+1” regimen (i.e., including one more immunisation than will be performed clinically). Testing may be carried out using test/consistency lots or final process pre-release materials. Additional safety testing may be required for batch release of GMP material, and should be confirmed with the NRA.

Other studies such as bio-distribution, persistence, or stability of the insertion/ deletion in a genetically modified organism may be conducted as relevant for the vaccine. An example of such safety studies is given in Arbues et al. 2013 for the live attenuated Mtb vaccine – MTBVAC. Such studies are not an absolute requirement and therefore may not be described in regulatory documentation but can be informed by best practice and an understanding of the specific product characteristics.