Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Stage/Gate B
Project Management
Main Activities
  • Update the Target Product Profile (TPP)
  • Prepare an integrated Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate B
CRITERIA REQUIRED
  • TPP revised
  • The PDP is drafted. It describes and integrates the main strategy across all functional areas, timeline and high-level estimated cost.
  • Activities, deliverables and criteria to pass Gate B agreed and finalised
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Guidance
Guidance

The integrated Product Development plan (PDP or iPDP) is introduced at Stage B and is used in conjunction with the TPP. The PDP is a living document that contains both an overview and history of the vaccine but also describes and integrates the main activities in all aspects of development and defines the roadmap to reaching the characteristics described in the TPP). The PDP lists activities leading up to at least the end of the First-in-Human (FIH) or Phase 1 clinical study. The recommendation is to organise the PDP per function (PM, characteristics, process, pre-clinical and regulatory), and ensure that they are integrated and connected. It contains a planning tool such as a Gantt chart which specifies tasks, timescales and their inter-dependencies, and a budget. Importantly the PDP contains an assessment of risks, mitigations and a gap analysis. Once the pieces of the development plan are integrated and connected, decision points and a critical path can be established.

Stage/Gate B
Business/ Legal/ Market
Main Activities
  • Describe Intellectual Property (IP) status
  • If necessary, identify potential partners to support development
CRITERIA REQUIRED
  • No major IP obstacles identified or strategy for resolution in place
  • As necessary, viable partners identified; Material Transfer Agreement (MTA) and other agreements established
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Guidance
Guidance

Intellectual Property (IP) is an important element in business. If not done already, it is wise at this early stage to analyse the status of IP of the technology or vaccine. This includes a review of the ‘state of the art’, what is known and published, and the status of own patents versus competition. It is important to identify any obstacle due to IP. The IP situation and strategy for resolution (of e.g. existing prior patent, uncertain freedom to operate) is defined at this stage and becomes part of the Product Development Plan (PDP).

The developer should consider if a partner will be needed in the near- or long-term to assist and support the development of the vaccine candidate. If so, a strategy for establishing and management of partnerships should be developed and this becomes part of the PDP.

An early analysis of the market potential of the product and the countries where it would be used should be performed and summaries should be part of the PDP. This analysis is important for TB vaccines which have a high global impact but an unvalidated commercial value. Further information is provided in an AERAS and TBVI publication TB vaccine Research and Development, a Business Case for investment.

Stage/Gate B
Product Characterization and quality
Main Activities
  • Document vaccine product stability
  • Select assays to monitor product quality, including an assay for potency
CRITERIA REQUIRED
  • Initial product stability defined
  • Feasible assays for product quality attributes selected, including for potency
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Guidance
Guidance

There is further characterisation of the vaccine substance / product for its identity, purity and potency. Evaluation of stability under the expected storage conditions must be performed at this stage, and this becomes a criterion for selection.

There is no correlate of protection for TB vaccines. This presents a challenge to determine the potency of vaccine candidate. Beside its concentration, several different marker assays are used as indicated above. The recently developed mycobacterial growth inhibition assay (MGIA) could be considered as a surrogate measure of a protective immune response.

The assays required for the testing of Critical Quality Attributes (CQA), the most relevant criteria for product quality with respect to safety and efficacy, are selected.

Stage/Gate B
Production process
Main Activities
  • Demonstrate feasibility of process at lab scale
CRITERIA REQUIRED
  • Process demonstrated to be feasible at lab scale
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Guidance
Guidance

The process parameters are explored and optimised at lab scale. Examples of parameters for cell culture are the expansion of cells, temperature, oxygen, pH, stirrer speed, and concentration of metabolites and vaccine product. For down-stream process (DSP), examples of parameters are temperature, flow rate, salt concentration, or column height for ion-exchange column chromatography. Critical parameters for each step of the process must be identified, and optimum set points and ranges defined experimentally. Critical are the yield, purity and stability of intermediate products.

Caution must be taken with raw material used for culture media and buffers. Lots of raw material should be evaluated to control input and identify, then avoid any variation in process performance and product quality. The same is true for the cells (expression system/ biological source organism) that are used to produce antigen, which must be stable for multiple production runs. A risk assessment would be appropriate to estimate the potential impact of process variations on product quality (based on literature, other development projects, and regulatory requirements).

The product quantity (yield) is optimised assuming that the product quality will not change, which will be demonstrated later. The selected set-points for the different process steps is confirmed with product testing in animals.

Guidelines on process and production of vaccines are: ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Nov 2000, including chapter 12 on Validation (ICH Q7), ICH Q8 Pharmaceutical Development, August 2009 (ICH Q8), ICH Q11 Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities), May 2012 (ICH Q11), ICH Q2, Validation of Analytical Procedures: Text and Methodology, Nov 2005 (ICH Q2) and Josefsberg and Buckland 2012.

Stage/Gate B
Preclinical Safety
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
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/Gate B
Preclinical Immunogenicity
Main Activities
  • Confirm and characterise immunogenicity
  • Develop hypothesis for immunological mechanism of action; design the Non-Human Primate (NHP) (or other model) study with appropriate outcomes, sample size, read-outs, data analysis plan, etc.
CRITERIA REQUIRED
  • Confirmed consistent immune response to antigens in at least one animal species
  • Hypothesis for immunological mechanism of action defined; synopsis of NHP study (or another advanced model) available
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Guidance
Guidance

Immunogenicity studies in Stage B should demonstrate that the candidate is immunogenic in the animal model chosen to confirm protection with the aim to link or correlate specific immune responses to protection. A more detailed characterisation of the immune response should be therefore be performed, for example identifying specific T-cell subsets or cytokine secretion profiles and, as with stage A the types of immune response should support the proposed mechanism of action of the candidate. The immune response profile identified in stages A and B should also be used to assist the design of studies in the NHP (or other advanced) model in Stage C. This would include informing the optimal immunisation protocol (e.g. the timing of prime and boost vaccinations) and to identify the most appropriate assays and samples to be taken. Immunogenicity studies in stage B might also include dose-finding in the context of live-attenuated mycobacteria in order to demonstrate that a relevant immune response is achieved with doses of vaccine that are safe and feasible (for example, for manufacture). The immunogenicity data generated in stage B would be used as part of the data package to select between the candidates chosen to advance to stage C.

Stage/Gate B
Preclinical Protection/efficacy
Main Activities
  • Confirm robust protection in a small animal Mycobcterium tuberculosis (Mtb) infection model in an independent lab or second animal model/ species
  • Prepare read-outs to evaluate protection in NHP (or other model) study
CRITERIA REQUIRED
  • Protection statistically better than a relevant benchmark (e.g. BCG or no vaccine, or best-in-class) reproduced independently in same species or confirmed in a second animal model
  • Immunogenicity and protection data support proposed mode of protection, and support the NHP (or another advanced model) study design
  • Read-outs for NHP (or other model) ready
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Guidance
Guidance

At Stage B, the emphasis is on confirming the protective efficacy of the candidate. Confirmation should be shown in a second animal model to demonstrate that the effect is biologically robust. This second model might be a guinea pig model or a mouse model which is more stringent e.g. involves a more virulent M. tuberculosis challenge, or uses a mouse strain which is more susceptible to disease. However, if this is not feasible for the candidate (for example, if a virus is known to be permissive in only one of the standardised animal models available), then independent verification of protection in the same animal model in another laboratory is acceptable. Regardless, it is imperative that the data are robust and that the protective effect can be reproduced. Studies aimed at elucidating the mechanism of action should be considered (e.g., T-cell depletion or passive antibody transfer). Head-to-head evaluation of vaccine candidates in independent laboratories is available via TBVI (TBVI services - standard mouse and guinea pig primary infection models, post-exposure vaccination models in mice and guinea pigs, mouse models involving challenge with clinical strains and NIH (NIAID/NIH pre clinical models - standard mouse and guinea pig models, therapeutic vaccination mouse models), where standardised and well-characterised models and study designs are employed to ensure that comparison of data is feasible and head-to-head testing is encouraged. Immunogenicity and efficacy studies conducted in Stages A and B should be used to support the design and execution of experiments in the advanced model(s) in Stage C, including the identification of a primary endpoint upon which Stage C studies will be powered.

Stage/Gate B
Regulatory
Main Activities
  • Identify regulatory path and potential barriers
CRITERIA REQUIRED
  • Regulatory strategy outlined, issues identified, and mitigation defined
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Guidance
Guidance

It is important that Regulatory becomes involved at this early stage of development to ensure that the proper guidelines are consulted and followed. Depending on the nature and the TPP of the TB vaccine under development (live genetically modified vaccines, vectored vaccines, protein-based vaccines etc.), the relevance of the general and specific WHO, ICH and Pharmacopeia guidelines will be evaluated to identify a general regulatory path and possible barriers and if feasible, mitigation will be defined.

For example, for live TB vaccines, the regulations and guidelines applicable to BCG will be taken into consideration. These are the US Pharmacopeia (USP) and European Pharmacopoeia (EP BCG vaccine, freeze-dried 0163) monographs and WHO recommendations on BCG vaccine, which specify safety, genetic stability, detailed characterisation of Master and Working seeds, antibiotic resistance marker, BSE/TSE exposure. For an antigen-based TB vaccine containing a new adjuvant, the WHO guidelines on the non-clinical evaluation of vaccine adjuvants and adjuvanted vaccines, 2103 will have to be taken into consideration.

Stage/Gate B
Clinical Development and Operations
Main Activities
  • Draft the Clinical Development Plan (CDP)
  • Look for existing epidemiology data in target population
CRITERIA REQUIRED
  • CDP drafted and clinical evaluation feasible
  • Existing epidemiology data identified and reviewed
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Guidance
Guidance

At this stage, a first draft of the clinical development plan (CDP) to generate safety and efficacy data supporting the TPP of the investigational TB vaccine should be prepared.

Two principal target populations are being considered for preventive TB vaccine development. (1)-Adolescents and adults who are largely contributing to the overall TB disease burden and who play a critical role in the transmission of Mtb and -(2) Neonates for whom a new TB vaccine either as a BCG replacing vaccine or as an infant boosting vaccine is aimed at improving upon current BCG vaccination. A third target population is represented by patients undergoing or completing treatment for active TB for whom a vaccine, given as an adjunct to antibiotic treatment, would increase the cure rate of treatment regimens and/or reduce the recurrence rate.

The CDP will start with safety and immunogenicity Phase 1 trials which comprise typical first administration to humans (First-in-Human, FIH) Phase 1 trial and subsequent first administration to the target population (Phase 1b trials) from TB-endemic regions. Larger Phase 2a studies will then establish the conditions of optimal safety and immunogenicity in the target population(s) related to the dose, formulation, immunisation schedule and route of administration that are to be selected for subsequent studies aimed at demonstrating the protective efficacy of the vaccine. Phase 2 studies may also include pre-proof of concept (POC) studies such as prevention of infection studies to help build a more robust clinical package before proceeding to large and resource-consuming efficacy trials.

The CDP will describe the evaluation of efficacy of the investigational vaccine in larger efficacy trials, i.e. Phase 2b proof-of-concept (POC) study(ies) and/ or Phase 3 pivotal trials, typically designed to assess the protective efficacy against TB disease.
These latter studies will also confirm the safety profile of the investigational vaccine. Given the significant need for a validated correlate of protection, the CDP should include a plan for the collection of samples to evaluate correlates of risk and/ or vaccine induced protection. See also clinical immunology.

Available epidemiological data on the incidence of the relevant endpoint (eg, Mtb infection and/or TB disease) in the targeted population should be reviewed, particularly in the specific populations where the trials are to be conducted, if available. These data are used to set assumptions for determination of potential sample size requirements for appropriate power to demonstrate the clinical benefit of the investigational vaccine and ensure that these are within limits of study feasibility. If adequate epidemiological data are not available, planning may need to be initiated for an epidemiologic study(ies)  to be conducted in advance of the Phase 2 pre-proof of concept (pre-POC) and Phase 2b clinical trials to inform protocol design and sample size calculations. See also Clinical Efficacy function.