Introduction
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 TPPs 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.
Considering best financial practices, and also for ethical consideration, funding of each clinical study should be fully secured before the start of the study.
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 immunization 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 both drug sensitive and drug resistant TB disease.
The objectives and the related clinical operations described in this guidance remain the same regardless of the vaccine type although for live attenuated and vector-virus vaccines Phase 1 studies may evaluate the potential for shedding.
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 ofefficacy of the investigational vaccine in larger efficacy trials, i.e. Phase2b proof-of-concept (POC) study(ies) and/ or Phase 3 pivotal trials, typicallydesigned to assess the protective efficacy against TB disease.These latter studies will also confirmthe safety profile of the investigational vaccine. Given the compelling needfor a validated correlate of protection, the CDP must include a plan for thecollection of samples to evaluate correlates of risk and/ or vaccine inducedprotection. 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.
- Draft an initial Clinical Development Plan (CDP)
- Look for existing epidemiology data in target population
- CDP drafted and clinical evaluation feasible
- Existing epidemiology data identified and reviewed
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. For more information on CDP refer to the introduction of function ‘clinical development and operations’
- Plan the pathway to FIH and anticipate subsequent Phase 2
- Draft Synopsis of Phase 1
- Engage with communities where clinical research will be conducted
- Update the Clinical Development Plan (CDP)
- Pathway to FIH and subsequent Phase 2 established
- Phase 1 synopsis drafted
- Community engagement programme initiated
- CDP updated
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.
Community Engagement planning is a significant strategic process designed to build long-term relationships and working collaborations with the people most affected by TB disease. Community engagement initiatives should be planned and implemented at all clinical sites where the studies will be conducted in preparation for the future studies and these initiatives will be ongoing through the entire development programme. They should include consultation over study design and dissemination of results to trial participants and the broader community. The communication of expected and unexpected outcomes is a significant part of this activity as well as general education about TB and vaccines. A relevant reference is the Good Participatory Guidelines for TB Vaccines.
First in Human (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 Phase1b studies will be designed and conducted in the target population in TB-endemic areas. At this stage the design of Ph1 and the CDP could be presented to NRA at a scientific advisory meeting, for more information refer to function ‘Regulatory’.
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.
TB vaccine target population 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).
- Prepare operations for FIH/Phase 1 (including completion of protocol, identification of principal investigator (PI), study site, etc.)
- Community engagement: educate on need for TB vaccines and clinical trials, obtain community input into Phase 1 design.
- Draft synopsis for subsequent Phase 2a, aiming at selection of doses, route, etc.
- Operations for FIH/Phase 1 prepared
- Input from the community obtained
- Draft Phase 2a synopsis prepared
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.
The community engagement activities will continue at this stage of the development for more information on community engagement, refer to guidance under Stage C.
- Conduct FIH/Phase 1
- Prepare operations for subsequent Phase 2a
- Provide and discuss results of earlier trials and obtain community input into Phase 2b trial design
- 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
- FIH/Phase 1 completed
- Protocol(s) and operations for Phase 2a prepared
- Community input obtained
- If warranted, pre-POC study prepared
- Plan for collecting adequate epidemiology study data for Phase 2b developed
- Synopsis for Phase 2b prepared
- CDP updated
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 (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.
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.
TB vaccine target population 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.
Safety and immunogenicity studies of concomitant administration with EPI recommended vaccine(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.
- 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
- Provide and discuss results of earlier trials and obtain community input into Phase 2b-3 trial design.
- Phase 2a completed; data available and analysed
- Pre-POC study completed
- Draft protocol and operation plan for Phase 2b available
- Adequate epidemiology data at sites of Phase 2b available
- Plan for engaging communities in the Phase 2b study and funding in place
- Community engaged on trial design
- CDP updated
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 study sites confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate sites are selected.
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.
TB vaccine target population 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.
- Complete operations and conduct Phase 2b
- Draft protocol for Phase 3
- Draft protocol for evaluation of clinical consistency (safety and immunogenicity) as a nested study within Phase 3 or a separate study
- Prepare operational plans for Phase 3, including selection of countries, study site, etc.
- Ensure epidemiology data are available at all study sites.
- Prepare plan and obtain funding for engaging communities in the Phase 3 efficacy trial in line with Good Participatory Practice guidelines
- Provide and discuss results of earlier trials and obtain community input into Phase 3 trial design.
- Update Clinical Development Plan (CDP)
- Phase 2b completed and data available.
- Protocol for Phase 3 drafted
- Protocol for clinical consistency study drafted
- Operational plans for Phase 3 prepared
- Epidemiology data available at all study sites
- Plan and funding in place for engaging communities in the Phase 3 efficacy trial
- Community engaged on trial design
- CDP updated
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.
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.
Phase 2b studies are completed allowing decision- making process regarding initiation of Phase 3 conduct.
TB vaccine target population 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.
- Prepare plan for community engagement for Phase 3, in line with Good Participatory Practice guidelines
- Complete operations and conduct Phase 3
- Perform safety and immunogenicity data analysis
- Document consistency of the various lots
- Prepare clinical study report (CSR)
- Initiate planning for Phase 4 studies
- Community engagement plan in place for Phase 3
- Phase 3 completed
- Safety and immuno data analyed
- Product consistency established
- CSR is available
- Draft Phase 4 plan established
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.
- Finalise clinical section of the MAA dossier
- Update protocol and update operational plans for Phase 4
- Provide and discuss results of previous trials, and obtain community input into Phase 4 trial design
- Clinical section of the MAA dossier finalised
- Protocol and operational plan for Phase 4 updated
- Community engaged on trial design
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.
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.
TB vaccine target population 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.
- Complete operations and conduct Phase 4 studies
- Phase 4 studies conducted
Phase 4 studies are initiated and carried out
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.