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
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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 largely contribute 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 is to be used either as a BCG replacing vaccine or as a BCG boosting vaccine. In the neonatal target population, the vaccine is aimed at providing improved efficacy and/ or an improved safety profile compared to BCG. For both populations, the indication is active immunisation for prevention of TB disease. 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 either increases the cure rate of treatment regimens and/ or reduces the recurrence rate. The indication is decrease of the recurrent TB disease rate and/ or increase of the cure rate of antibiotic treatment regimens. Consideration may also be given to investigating the efficacy of candidate TB vaccines to shorten treatment duration and/ or reduce the number of antibiotics. These indications apply to the prevention of both drug sensitive and drug resistant TB disease.

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 subsequently first administration to the target population (Phase 1b trials) in 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.

As the evaluation of vaccine-induced protection against TB disease requires a large study population and long follow up, alternative endpoints related to more frequent events may be utilised to provide evidence that the vaccine-induced immune response is biologically functional. Hence, Phase 2 studies may also include pre-proof of concept (pre-POC) studies such as prevention of infection(POI) or prevention of recurrence (POR) studies to help build a more robust clinical package before proceeding to large and resource-consuming efficacy trials (ref Ellis et al.).

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 compelling need for a validated correlate of protection, the CDP must 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 the limits of study feasibility. If adequate epidemiological data are not available, an epidemiologic study(ies) should 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
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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 should be 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, BCG vaccinated adults with no evidence of exposure to TB. Subsequent Phase 1b studies will be designed and conducted in the target population 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 relevant information that has become available from the pre-clinical programme and/ or general advances in the field of TB vaccine research.

Target-specific considerations

Adolescent/ adult vaccine: FIH studies could be planned to evaluate the safety and immunogenicity of the investigational vaccine in BCG naïve and BCG vaccinated individuals, who have no evidence of latent TB infection, sequentially in the same study. In addition, Phase 1b studies are designed to evaluate the safety and immunogenicity of the investigational vaccine in subjects from endemic areas who have evidence of latent TB infection.

Neonate/ infant vaccine: Phase 1b studies are designed to evaluate the safety and immunogenicity of the candidate vaccine in neonates in TB endemic areas. Study design is dependent on the vaccination strategy, BCG replacement or BCG boosting vaccine.  

Therapeutic vaccines: Phase 1b studies might not be required if safety and immunogenicity data are available from BCG vaccinated Mtb infected individuals. Proceed to Phase 2a (dose and regimen selection).

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
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Guidance

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

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

FIH and Phase 1b protocols completed and sites selected as per generic criteria.

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
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Guidance

The FIH trial is completed during this stage, as well as Phase 1b 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 (pre-POC), e.g. prevention of infection (POI, Nemes et al) 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 to be considered for Phase 2b and/ or 3 trials.

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

Target-specific considerations

Adolescent/adult vaccine: A plan for a Phase 2b trial to assess the protection against pulmonary TB Disease(POD) should also be developed at this stage. POD Phase 2b could be conducted among individuals considered at higher risk of disease to reduce sample size and study duration, e.g. latently infected (QFT+) individuals, health care workers, or household contacts. The CDP should be updated to reflect how a broader label, i.e. beyond the POC population, will be achieved in Phase 3.  

Consideration could be given in the development plan to the possibility of licensing POR as the vaccine indication. As POR studies are smaller than prevention of disease (POD) trials (due to higher incidence of recurrence in patients recently treated for TB compared to the incidence TB disease in the general population), this may be a more rapid path to licensure and it will address a significant unmet medical need.

Neonate/infant vaccine:  FIH and Phase 1b studies in neonates from endemic countries are completed during this stage. As per generic plan, the dose and regimen of a BCG replacement or a BCG boosting vaccine will be evaluated during safety and immunogenicity Phase 2a studies. Definition of the control differs by vaccination strategy; for BCG replacement, BCG or the investigational vaccine only are administered at birth in the control and test group, respectively and for BCG boosting, the control group receives a placebo and the test group the investigational vaccine, both administered at a pre-defined time after birth BCG vaccination.

Safety and immunogenicity studies of concomitant administration with EPI recommendedv accine(s) should be planned to be conducted before or during Phase 2b studies.

Therapeutic vaccine: Safety and immunogenicity Phase 2a studies are designed to define the optimal dose level and timing of therapeutic vaccination relative to antibiotic treatment.

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
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Guidance

Phase 2a studies are completed during this stage. Safety and immunogenicity data are available for analysis and should provide data supporting the vaccine formulation, dose and regimen selected for subsequent efficacy trials. Whenever conducted, the 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 stud ysites confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate sites are selected.

Target-specific considerations

Adolescent/adult vaccine: Whenever considered, pre-POC studies are completed and provide efficacy data that help decision-making regarding further development, ie Phase 2b and or Phase 3 efficacy trials.

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
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Guidance

The 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 study is finalised and the identified study sites are prepared for conducting the Phase 3 study. Epidemiological data at the potential study sites are available to confirm the site selection and to determine Phase 3 sample size. The Phase 3 study 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 the Phase 3 study.  

Phase 2b studies are completed allowing decision- making process regarding initiation of Phase 3 conduct.

Target-specific considerations

Adolescent/ adult vaccine: As pre-vaccination screening for infection status cannot be routinely considered for programmatic reasons, it is critical that Phase 3 study populations include both QTF- and QTF+ individuals. Although study design and power should ideally be for protective efficacy against TB disease in both strata, such a study would be extremely large and complex making it unlikely to be feasible. If powered to show vaccine efficacy against primary endpoint in QTF + strata, the study should offer an acceptable assessment of safety and trend for efficacy in QTF- strata.

The study population age should be consistent with the predominant age range in TB disease burden in the region.

Neonate/infant vaccine: Safety and immunogenicity data from study(ies) of concomitant administration with EPI vaccines should be available before conduct of Phase 3, or a rationale developed and agreed with National Regulatory Authorities justifying why this is not required.

Therapeutic vaccines: The Phase 3 study should be designed and powered to evaluate POR as primary endpoint. Separate analysis by relapse and reinfection could also be considered. The increase in the cure rate of antibiotic treatment regimens is likely to be a very difficult endpoint to reach under clinical trial conditions.

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
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Guidance

The Phase 3 study has been completed; safety and efficacy data are analysed. The complete study report is prepared. If vaccine consistency has not been established at this stage, a study of safety and immunogenicity consistency of lots should be carried out.

Draft a plan for Phase 4 studies to assess vaccine safety and effectiveness in field conditions and in populations that have not yet been studied during Phase 3 studies.

Stage 
I
Register vaccine with relevant Regulatory Authorities
Gate 
I
Obtain MA and Progress to launch
Main Activities
  • Finalise clinical section of the MAA dossier
  • Update protocol and update operational plans for Phase 4
CRITERIA REQUIRED
  • Clinical section of the MAA dossier completed
  • Protocol and operational plan for Phase 4 updated
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Guidance

The different sections related to the clinical documentation of the dossier are prepared for inclusion in the MAA dossier.

Relevant Phase 4 study protocols are drafted to assess vaccine safety and effectiveness in terms of magnitude and duration of vaccine-induced protection under field conditions.

Target-specific considerations.

Adult vaccine:

Safety and effectiveness Phase 4 studies should also be considered in relevant populations that have not yet been fully studied, e.g. QTF- population to confirm Phase 3 efficacy trend or that would not have been studied in Phase 3 e.g. elderly, HIV-infected adults.

Neonate/infant vaccine. Safety and protective efficacy should also be considered in sub populations such as pre-term neonates, neonates born to HIV-infected mothers that may not have been assessed in Phase 3 trials.    

Therapeutic vaccines. Phase 4 effectiveness studies will be designed to confirm the increase in cure rate of antibiotic treatments, to evaluate potential additional benefits of therapeutic vaccination such as antibiotic treatment shortening, and / or reduction in toxicity of antibiotic regimen.

Stage 
J
Launch
Gate 
J
Implement vaccination programs
Main Activities
  • Complete operations and conduct phase 4 studies
CRITERIA REQUIRED
  • Phase 4 studies initiated
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Guidance

Phase 4 studies are initiated and carried out.