Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Stage/Gate E
Project Management
Main Activities
  • Update the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate E
CRITERIA REQUIRED
  • TPP updated with data from Phase 1
  • PDP updated to include (a) details by functional area to prepare for phase 2; (b) marketing aspects ; (c) summaries of data collected to date, (d) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate E agreed and finalised
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Guidance
Guidance

The TPP and PDP are updated and include information on safety and immunogenicity data from Phase 1. While most Phase 1 trials are performed in a single clinical site, Phase 2 studies maybe multi-centric, and could involve multiple countries. As clinical development progresses, the need for additional resources in clinical and regulatory aspects, and coordination is more complex. The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new CMC campaign. The PDP anticipates the need for an efficacy study (Phase 2b) and should describe its design, overall operations and resources needed and regulatory strategy for approvals. Moreover, the PDP now integrates activities related to Marketing and ideally a market analysis, the identification of targeted countries, and access strategy. The Gantt chart and budget are updated.

Stage/Gate E
Business/ Legal/ Market
Main Activities
  • If necessary, identify potential partners to support late development (Chemistry, Manufacturing and Controls (CMC), scale-up validation)
CRITERIA REQUIRED
  • As necessary, viable partners identified; contractual agreements and other agreements established
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Guidance
Guidance

As the cost of development and the need for capacity increases, if necessary, potential partners to support mid and late clinical (CMC, scale-up validation) development are sought.

Stage/Gate E
Product Characterization and quality
Main Activities
  • Fine tune (if needed) quality control (QC) assays
  • Qualify and/or validate QC procedures
  • Characterise newly produced drug substance (DS) and drug product (DP)
  • Perform stability studies
CRITERIA REQUIRED
  • QC assays refined (if needed)
  • Plan to ensure validation of QC procedures established
  • DP and DS pass the tentative product specifications recorded in the Target Bill of Testing (BOT); impact of changes and deviations on DS and DP are documented
  • Stability data sufficient to support clinical trial
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Guidance
Guidance

During Phase 1, the assays for CQA continue their qualification, progressing to validation. The assays used for product characterisation could be slightly modified, to improve the sensitivity or accuracy of the test. This should not change the qualification or later validation status of the assays. Up to this point, the product reference would be from well described R&D production runs, and used to standardise assays. It could now be replaced by a GMP compliant reference.  
The assays are used to release any new GMP material produced, or document changes in the drug product (within certain limits), and in the continuing stability studies.

Stage/Gate E
Regulatory
Main Activities
  • Prepare and submit Clinical Trial Application (CTA) and obtain approval for First-in-Human (FIH)/Phase 1
  • Propose regulatory pathways for global licensure
CRITERIA REQUIRED
  • CTA for FIH/Phase 1 submitted and approval obtained
  • Proposed regulatory pathways aligned with CMC, clinical and marketing
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Guidance
Guidance

The regulatory strategy towards licensure in the various potential markets is developed at this stage. It goes hand-in-hand with the development of a market access strategy.

There are three potential pathways to licensure, relevant to TB vaccines that will guide and influence the regulatory strategy:

a) WHO prequalification once licence has been obtained from a stringent Regulatory Authority (or EMA article 58 positive opinion). Prequalification is a service provided by WHO (WHO prequalification) to health agencies that purchase vaccines, to determine the acceptability, in principle, of vaccines from different sources for supply to these agencies. It allows  GAVI-eligible low income countries, non-GAVI eligible middle income countries or PAHO (Pan American Health Organisation) countries to be reached:
      • The WHO prequalification ensures that vaccine efficacy data and studies are relevant to the target population, that vaccines used in immunisation programmes are safe and effective and meet the specific needs of the programme (programmatic aspects)
      • WHO prequalification process: review of general production process and quality control procedures, testing of consistency of lots and audit of the manufacturing facilities with observers from the responsible agency.

b) Application for national marketing authorisation (in-country licensing) (e.g. South Africa).

c) In-country manufacturing and licensing (e.g. China, India).

In Africa, the WHO African Vaccine Regulatory Forum (AVAREF) can be used as a collaboration platform enabling regulators, ethics committees and sponsors to reach consensus on key ethical and regulatory questions. For more information about AVAREF refer to Africa Network.

Stage/Gate E
Clinical Development and Operations
Main Activities
  • Conduct FIH/Phase 1
  • Prepare operations for subsequent Phase 2a
  • If warranted, prepare for pre-Proof of Concept (PoC) study (e.g., Prevention of Infection (POI) study)
  • If necessary, prepare a plan to obtain adequate epidemiology data in target population for Phase 2b
  • Draft synopsis for Phase 2b
  • Update CDP
CRITERIA REQUIRED
  • FIH/Phase 1 completed
  • Protocol(s) and operations for Phase 2a prepared
  • If warranted, pre-POC study prepared
  • Plan for collecting adequate epidemiology study data for Phase 2b developed
  • Synopsis for Phase 2b prepared
  • CDP updated
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Guidance
Guidance

The FIH trial is completed during this stage, as well as Phase1 b in primary target populations.

Study protocols for Phase 2a studies to establish the optimal dose, formulation, route of administration and schedule of immunisation are developed and the PIs and study sites are selected.

Pre-proof of concept trials, e.g. prevention of infection (POI) or prevention of recurrence (POR), study plans should be advanced at this stage, including the development of study synopses as appropriate.
A plan should also be drafted to generate reliable epidemiological data on TB disease endpoints in the target population in different regions and at the different study sites considered for Phase 2b and/or 3 trials.

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 E
Clinical Safety
Main Activities
  • Analyse FIH/Phase 1 safety data
CRITERIA REQUIRED
  • Safety profile of selected doses or regimen of FIH/Phase 1 supports subsequent Phase 2a
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Guidance
Guidance

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) indicate an acceptable reactogenicity profile of the different vaccine doses which are being considered for Phase 2a studies. Safety concerns have not been identified.

Stage/Gate E
Clinical Immunology
Main Activities
  • ¥ Analyse FIH/Phase 1 immunogenicity data
  • Characterise immune responses using primary and exploratory endpoints
  • Prepare a collection and storage plan for relevant bio-specimens from Phase 2a based on primary and exploratory immunogenicity
CRITERIA REQUIRED
  • Evidence of sufficient immune response based on primary endpoints at safe vaccine dose level(s) in FIH/Phase 1
  • Potential biomarkers for Phase 2a identified; plan for their evaluation prepared
  • Biobanking plan established
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Guidance
Guidance

Immunogenicity data of the Phase 1 and other Phase 1b studies will be analysed to characterise immunogenicity. The elicited immune responses must provide evidence that the candidate induces vaccine antigen(s)-specific immune responses and an evaluation must be made of whether these responses are sufficient to progress development of the candidate vaccine. In addition to safety, immunogenicity will guide the selection of the dose(s) to be further evaluated in Phase 2a study(ies).

Wherever possible a biomarker plan must be prepared prior to embarking on clinical efficacy studies: plans should be made for samples to be collected and bio-banked for future correlates analyses – these samples will be vital for the potential discovery of correlates of risk and/or protection.

Stage/Gate E
Clinical Efficacy
Main Activities
  • Define endpoints for pre-POC study (if warranted) together with endpoints for efficacy in a Phase 2b
CRITERIA REQUIRED
  • Endpoints for pre-POC or first efficacy trial defined
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Guidance
Guidance

Pre-proof of concept trials are considered in subjects who are at high risk of an outcome of interest such as Mtb infection. Although Mtb infection would not be seen as a licensable clinical endpoint by a stringent regulatory authority, prevention of infection (POI) would indicate biological activity of vaccine-induced immune response which could be seen as a clinically relevant biological signal and potential indicator of vaccine efficacy.

Another pre-POC pathway is represented by prevention of recurrence (POR) trials in patients recently treated for TB and cured, as these individuals are at high risk of recurrence (by a combination of endogenous relapse and exogenous reinfection).

The study design for Phase 2b will reflect the statistical hypothesis: usually superior efficacy over either placebo or benchmark vaccine (e.g. BCG). The magnitude of superiority should reflect the expected improvement in public health outcomes. The preferred primary endpoint for Phase 2b should be bacteriologically confirmed i.e., culture and/or GeneXpert+) cases of TB disease using standardised case definition (WHO definitions of TB 2014). Culture confirmation or WHO approved rapid diagnostic (WRD) such as Gene Xpert technology based test is required rather than the less sensitive and less specific smear microscopy.

Stage/Gate E
Market Access
Main Activities
  • Based on TPP identify potential list of targeted countries (early, middle and late adopter countries) and considering income (low, average, high)
  • Collect epidemiological, burden of disease data and market data in targeted countries for a preliminary market assessment
CRITERIA REQUIRED
  • Initial list of targeted countries established, with rationale
  • Preliminary market assessments & business strategy available for targeted countries
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Guidance
Guidance

With the decision to move the candidate(s) into clinical development, a formal market assessment should be performed at this stage. It will include the medical need (from epidemiology data, including incidence and disease burden), market characteristics and dynamics (demand, market size, competition, procurement and delivery processes), and positioning of the vaccine (versus Standard of Care, niche indications, competitive advantages, match between product and demand). A market strategy and communication plan should be drafted and be part of the PDP. Target countries for vaccination implementation should also be re-evaluated and defined. A comprehensive review of recent literature would be a relevant way to gather these data (see for example Tu et al., 2012).