Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Stage/Gate C
Project Management
Main Activities
  • Review the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate C
CRITERIA REQUIRED
  • TPP revised, if necessary
  • PDP updated to include (a) details by functional area to prepare for First-in-Human (FIH) and other Phase 1 studies; (b) summaries of data collected to date; (c) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate C agreed and finalised
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Guidance
Guidance

As the project prepares for clinical phases, the TPP and the PDP are updated. The PDP includes new information from characterisation and process activities and data generated in pre-clinical studies. It should include details of the preparation for the Phase 1, first-in-human (FIH) study, with its design (population, doses, schedule etc.) or a synopsis of the protocol. It should also include other Phase 1 studies, if planned. The Gantt chart and budget are updated.

Stage/Gate C
Business/ Legal/ Market
Main Activities
  • Establish acceptable Intellectual Property (IP) position
CRITERIA REQUIRED
  • Freedom to operate investigated and an acceptable level of risk demonstrated
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Guidance
Guidance

A Patent Attorney should evaluate the freedom to operate and provide an opinion on risk to further confirm/solidify an acceptable IP position.

Stage/Gate C
Product Characterization and quality
Main Activities
  • Optimise and finalise vaccine composition and route of administration
  • Develop release assays and stability tests
  • Prepare batch release
CRITERIA REQUIRED
  • Vaccine characteristics critical for vaccine immunogenicity (e.g., antigen sequence, adjuvant, delivery system, route of administration) finalised
  • Target Bill of Testing (BOT) defined with target specifications for final product, drug substance (potency), excipients, impurity profile and product composition
  • Quality control (QC) tests selected and their feasibility demonstrated, incl. for potency/ relevant biological activity, identity, purity, and stability
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Guidance
Guidance

The assays selected for quality control and characterisation are developed, together with target specifications, for identity, potency, purity etc. These quality parameters of the substance and the product are referred as Bill of Testing (BoT), or Quality Target Product Profile (QTPP).

Note: the raw materials used for production of the substance and the product should be checked before being used in the lab. This quality control procedure is mandatory for current Good Manufacturing Practice (cGMP) operations. Certificates of Analysis of raw material must be collected and assays with target specifications selected for release.

Stage/Gate C
Production process
Main Activities
  • Develop and assess feasibility of manufacturing process at pilot scale (e.g. multiple pilot scale runs)
  • Evaluate real-time and accelerated stability on a pilot-scale lot of a Drug Product (DP)
  • Identify a Good Manufacturing Practices (GMP) facility
CRITERIA REQUIRED
  • Reproducibility acceptable and process at pilot scale fixed. If needed, minor revisions to the process can be applied, within the process specifications
  • Quantity and quality of product meets pre-defined feasibility criteria (TPP)
  • First stability data meets pre-set feasibility criteria (TPP)
  • GMP facility identified
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Guidance
Guidance

The process is scaled up from lab-scale to pilot, at a scale calculated to generate sufficient material for toxicity studies and Phase I / 2 clinical studies.

MCB and WCB, or a combination of Master and Working Virus Seed Lot combined with a MCB and WCB of complementary host cells, are manufactured according to cGMP guidelines or equivalent quality level. After determining feasibility of the pilot-scale process performed with cells from the WCB, vials are sent for release testing.

Standardised production runs at pilot scale (pre-GMP runs) will confirm feasibility and reproducibility. Indeed, by demonstrating that repeated runs can be performed within certain ranges around the set-points for the relevant process parameters, the reproducibility of the process (or process steps) is established, as required for the pilot process according to GMP guidelines. The variation obtained in parameters which are considered critical should be within the ranges tested at lab scale. At the end of this Stage, the selected process now, at pilot scale, can produce the right quantity of product with the correct quality (drug substance and contaminants) and, no further adjustments are required.

At the end of this Stage, the process is fixed for manufacturing of Phase 1 GMP material. Later changes in the process can be required. It will have to be demonstrated that the implemented process changes do not affect the product quality attributes (product comparability). For TB vaccine candidates, later changes in the production process would likely need clinical bridging studies.

Stage/Gate C
Preclinical Safety
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
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/Gate C
Preclinical Immunogenicity
Main Activities
  • Confirm immunogenicity against relevant benchmark
  • Expand immunogenicity (Th1, ,Th17, γδ T cells etc.) to explore mechanism in same species used to demonstrate efficacy
CRITERIA REQUIRED
  • Immune response against relevant benchmark established
  • Immune mechanisms and breadth of immune response explored
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Guidance
Guidance

Pre-clinical studies in Stage C are typically conducted in NHP or another highly relevant (and often resource-intensive) model. As the results of these studies are used as key gating criteria for advancement into clinical trials, they should be conducted as carefully and thoroughly as possible. Importantly, before proceeding to a challenge study, the vaccine dose and regimen should be optimised for the model selected and based upon the proposed mechanism of action (for example, dose or route selection for an adenovirus-based candidate may be based upon CD8+ T-cell responses characterised by intracellular cytokine staining, see Hokey et al., 2014). Immunogenicity evaluations should then be expanded in the challenge study. In addition to the inclusion of assays to confirm vaccine “take,” additional exploratory assays should be included to explore the mechanism of action and identify potential correlates of protection. These may include the use of multiple or more extensive intracellular cytokine staining panels (to characterise Th1, Th17, gamma delta T-cells, etc.), antibody assays, and systems biology approaches. In order to conserve resources, samples for such exploratory assays can be collected and stored for analysis pending the challenge outcome. A recommendation is to consider the use of technologies provided by providers of platforms such as transcript- or other omics, e.g., GH-VAP (ghvap.org), and TRANSVAC (transvac.org), which offer unbiased and specialised expert assessments. Finally, consideration should be given to how key assays might bridge to the clinic.

Stage/Gate C
Preclinical Protection/efficacy
Main Activities
  • Confirm protection or Proof of Concept (PoC) (Note: the animal models for evaluation should be justified based on candidate’s proposed mechanism of action)
CRITERIA REQUIRED
  • Protection vs Mtb challenge statistically better than BCG and/or relevant benchmark using primary endpoint in 2 animal models, as demonstrated by a read-out with high statistical power for the group size: 1. Protection vs Mtb challenge in a small animal model confirmed, 2. Protection vs Mtb challenge in a Non human primate (or justified, human-relevant, advanced animal model) confirmed
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Guidance
Guidance

Given the close similarity of non-human primates (NHP) to humans, data generated in NHP models are the most likely to predict clinical immunogenicity and efficacy and therefore efficacy data generated in an NHP model will provide the greatest confidence for funders / stakeholders to invest in further development. Studies conducted in NHP allow parallels to be drawn directly with data generated in humans which (i) inform the design of early clinical studies for example by providing information on vaccine doses/ routes/ regimen/ type of immunological read–out and (ii) provide added significance to the clinical immune responses because they can be correlated to a relevant signal of protection. Ethical and financial considerations restrict the testing of candidates in NHP to those which have the greatest potential, hence the system of screening in more tractable animal models in stages A and B is designed to identify the most promising of vaccines. The global capacity for candidate evaluation in NHP has been increased and there are now standardised methodologies for measuring vaccine efficacy across different NHP sites (Laddy et al., 2018). Thus, there is an expectation and encouragement that protection in NHPs should be demonstrated in order to pass Gate C. However, there may be situations where a different, advanced animal model would be equally appropriate. Examples where alternative models may be pursued include using cattle field trials to demonstrate prevention of naturally acquired infection or using prevention of relapse models. Animal models for TB vaccines are still being developed and refined and important developments (such as the establishment of a controlled human challenge system) may have an impact upon the selection of the model used but at stage C, it is imperative that the model used must be justifiable and highly relevant to the nature and TPP of the vaccine and must be robust and reproducible so studies in non-standard models which are under development is discouraged. A primary endpoint should be selected and documented before initiation of the study, and the study adequately powered to produce clear, statistically significant results. Without setting specific levels of protection against myriad endpoints that would be required to support advancement of a candidate into the clinic, there is an expectation that protection be statistically significant. Investigators are encouraged to confer with the CTVD’s Nonhuman Primate Research Community for advice on the design and execution of NHP challenge studies.

Stage/Gate C
Regulatory
Main Activities
  • Identify regulatory path and possible barriers
  • Consult Regulatory Authority (RA) with questions for scientific advice in a pre-Phase 1 meeting
CRITERIA REQUIRED
  • Regulatory input/scientific advice obtained
  • Regulatory risks assessed; no major roadblocks to product and clinical development indicated
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Guidance
Guidance

Consultation with a regulatory agency for formal advice will be most valuable in the pre-Phase 1 stage, prior to starting clinical development of a new TB vaccine. Data generated to this point are presented, and advice is requested via specific questions. Topics for discussion and  agreement with the regulatory agency usually include:
• Manufacturing process and controls, characterisation of the antigen, release specifications for the MCB/WCB and drug substance/product and stability specifications. These discussions would include the choice of the relevant Quality Control and characterisation assays – especially for potency
• Pre-clinical and toxicology study programme
• Synopsis of protocol for Phase 1 and summary of clinical development plan.

Of note, the second Geneva Consensus meeting (Walker et al., 2010) has given recommendations for novel live TB vaccines and can be referred to.

Stage/Gate C
Clinical Development and Operations
Main Activities
  • Plan the pathway to FIH and anticipate subsequent Phase 2
  • Draft Synopsis of Phase 1
  • Update the Clinical Development Plan (CDP)
CRITERIA REQUIRED
  • Pathway to FIH and subsequent Phase 2 established
  • Phase 1 synopsis drafted
  • CDP updated
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Guidance
Guidance

Activities in stage C are based around planning and preparation for FIH trial and subsequent Phase 1b trials that are designed to include target population individuals, in order to provide the data needed to support preparation and conduct of Phase 2 studies.

FIH Phase 1 study design typically is double-blind, randomised controlled and dose -escalating to evaluate safety and immunogenicity of the investigational vaccine in a limited number of healthy, BCG naïve and, potentially, vaccinated adults with no evidence of exposure to TB. Subsequent Phase1b studies will be designed and conducted in the target population. These trials will be conducted in TB-endemic areas.

A study synopsis for Phase 2a studies to select a dose(s) for further development should be drafted.

The CDP will be updated to reflect any new information that has become available from the pre-clinical programme and/or general advances in the field of TB vaccine research.

Stage/Gate C
Clinical Safety
Main Activities
  • Define the safety endpoints for Phase 1
CRITERIA REQUIRED
  • Safety endpoints for Phase 1 defined
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Guidance
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/Gate C
Clinical Immunology
Main Activities
  • Define the primary and exploratory immunogenicity endpoints based on putative mechanism of immune protection (“potential immune correlates”) for Phase 1
CRITERIA REQUIRED
  • Plan drafted to develop assays to measure primary and exploratory immunological endpoints
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Guidance
Guidance

Vaccine immunogenicity may be a co-primary or secondary objective of Phase 1 studies.