Function

The clinical development plan (CDP) of a novel TB vaccine candidate should describe the entire clinical programme which includes the successive clinical trials (Phase 1, 2a, 2b, 3) needed to generate safety and efficacy data supporting the TPP of the investigational TB vaccine. Each clinical programme should be developed in line with the sponsor’s Target Product Profiles(s) (TPP(s)) for the candidate vaccine, which may include one or more target age groups and indications. The aim of clinical operations is to conduct clinical trials in accordance with the clinical development plan.

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
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
Plus Icon
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.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
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
Plus Icon
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 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Prepare operations for FIH/Phase 1 (including completion of protocol, identification of PI and study site etc)
  • Draft synopsis for subsequent Phase 2a, aiming at selection of doses, route, etc.
CRITERIA REQUIRED
  • Operations for FIH/Phase 1 prepared
  • Draft Phase 2a synopsis prepared
Plus Icon
Guidance

Study protocol for subsequent Phase 1b trials are completed. The Principle Investigators (PIs) and study sites for these trials also selected.

Study synopsis for Phase 2a study(ies) should be developed.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
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
Plus Icon
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 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • Complete operations and conduct subsequent Phase 2a study(ies)
  • Conduct Pre- Proof of Concept (POC) study (if part of Clinical Development Plan (CDP))
  • Prepare protocol and operational plans for Phase 2b
  • Collect adequate epidemiology data in target population and in the countries of clinical studies
  • Prepare plan and obtain funding for engaging communities in the phase 2 studies in line with Good Participatory Practice guidelines
  • Update CDP including synopsis for Phase 2b-Phase 3
CRITERIA REQUIRED
  • Phase 2a completed; data available and analysed
  • Pre-POC study completed
  • Draft protocol and operation plan for Phase 2b available
  • Preliminary epidemiology data at sites of Phase 2b available
  • Plan and funding in place for engaging communities in the Phase 2 studies.
  • CDP updated
Plus Icon
Guidance

Phase 2a studies are completed during this stage. Safety and immunogenicity data are available for analysis and should demonstrate support for the vaccine formulation, dose and regimen selected for subsequent efficacy trials. Whenever conducted, pre-POC study is also completed.

The study protocol for Phase 2b is prepared, and study sites included in the Phase 2b are operational. Epidemiological data that have been collected at study sites confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate sites are selected.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Complete operations and conduct Phase 2b
  • Draft protocol for Phase 3
  • Prepare operational plans for Phase 3 (including selection of countries, study site, etc)
  • Prepare plan and obtain funding for engaging communities in the Phase 2b efficacy trial in line with Good Participatory Practice guidelines
  • Update Clinical Development Plan (CDP)
CRITERIA REQUIRED
  • Phase 2b completed and data available
  • Protocol for Phase 3 drafted
  • Operational plan for Phase 3 prepared. Epidemiology data available at all study sites
  • Plan and funding in place for engaging communities in the phase 2b efficacy trial
  • CDP updated
Plus Icon
Guidance

Phase 2b study is completed during this stage and data are available for statistical analysis. If data indicate protective efficacy equal to or greater than pre-set Go/ NoGo criteria, a study protocol for Phase 3 is finalised and the identified study sites are prepared for conducting the Phase 3 study. Epidemiological data at the potential study sites are available and utilised in site selection and to determine Phase 3 sample size. Phase 3 should be conducted with at least one vaccine lot produced at the intended scale for marketing and its design should consider a clinical assessment of vaccine consistency.  

The CDP will be updated to reflect the Phase 2 b data and possible consequences on Phase 3 study.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Complete operations and conduct Phase 3
  • Plan and obtain funding for community engagement for Phase 3, in line with Good Participatory Practice guidelines
  • Initiate planning for Phase 4 studies
CRITERIA REQUIRED
  • Phase 3 completed and data available
  • Community engagement plan and funding in place for Phase 3
  • Product consistency established
  • Draft Phase 4 plan established
Plus Icon
Guidance

Phase 3 study has been completed and data are available for analysis. If vaccine consistency has not been established at this stage, a safety and immunogenicity consistency lots study should be planned as well as post-marketing studies committed.