The TPP and PDP are updated and include data on safety and immunogenicity from Phase 1. While most Phase 1 studies are performed in a single clinical site, Phase 2 studies are multi-centric, and often involve multiple countries. As clinical development progresses, the need for additional resources in clinical and regulatory aspects increases, and coordination is more complex. The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new Chemistry, Manufacturing and Controls campaign with GMP production for clinical trial material. The PDP anticipates the need for proof of concept efficacy study (Phase 2b) and describes its design, overall operations and resources needed, and regulatory strategy. 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.
As the cost of development and the need for capacity increases, if necessary, potential partners to support mid and late manufacturing and clinical development are sought. Market analysis and assessments are refined according to availability of new data.
During Phase 1, the assays for Critical Quality Attributes (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 be 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 to document changes in the drug product (within certain limits), and in the continuing stability studies.
The regulatory strategy depends on the indication sought (preventive vaccine or therapeutic vaccine) and goes hand-in-hand with the development of a market access strategy.
For neonates/infant and adolescent/adult vaccines there are different pathways to Marketing Authorisation. For most countries, Marketing Authorisation can be obtained through an application for national Marketing Authorisation (in-country licensing). 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. For reference, Dellepiane et al, 2018. For GAVI (Global Alliance for Vaccines and Immunisation, GAVI, the Vaccine Alliance) eligible low-income countries, non-GAVI eligible middle-income countries or PAHO (Pan American Health Organisation) countries, application for WHO prequalification can be followed once a Marketing Authorisation has been obtained from a stringent Regulatory Authority (or EMA article 58 positive opinion, EMA/ CHMP evaluation done in collaboration with WHO under Article 58 of Regulation (EC)No. 726/2004). 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.
For therapeutic TB vaccines, the regulatory strategy will greatly depend on the countries where the vaccine is to be marketed. In countries which hold stringent Regulatory Authorities, a full Marketing Authorisation will be required. Of note, if the indication sought concerns MDR- and XDR-tuberculosis whose prevalence is below 5/10 000, an orphan drug status designation may be applied for in those countries which have implemented a combination of legislations, regulations and policies for orphan drugs, e.g. the European Union, USA, Japan, Australia. Such legislation includes a variety of incentives to encourage orphan drug research, development and marketing. These often include tax credits for research costs, grants, waived application fee, several years of marketing exclusivity that prevents marketing approval of generic drug or brand name for the same rare disease indication, free scientific advice, fast track/ priority review for Marketing Authorisation and pre-licensing access initiatives, including off-label and compassionate use programmes. For developing countries, a meeting with WHO will have to be organised quite early to discuss the possibility for WHO to prequalify a therapeutic TB vaccine because, unlike BCG, therapeutic TB vaccines are not on the current WHO vaccine prequalification priority. The regulatory strategy will thus depend on the acceptability or non-acceptability by WHO to prequalify therapeutic TB vaccines.
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.
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.
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. No safety concerns have been identified.
Adolescent/ adult vaccine: Safety data in both QTF- and QTF+ adults are required.
Neonate/ infant vaccine: Develop a plan to assess safety in HIV exposed, as well as unexposed neonates and infants. For a neonatal BCG-replacement vaccine candidate, plan to evaluate safety in comparison to BCG in HIV exposed neonates.
Immunogenicity data of the Phase 1 and other Phase 1b studies will be analysed to characterise immunogenicity using primary and exploratory endpoints. 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.
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 may 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 inpatients recently treated for TB and cured, as these individuals are at high risk of recurrence (by endogenous relapse or 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 testis required rather than the less sensitive and less specific smear microscopy.
Adolescent/ adult vaccine:The study design for Phase 2b will reflect the statistical hypothesis of superior efficacy over placebo as there is no current recommendation for BCG booster immunisation. The magnitude of efficacy should be consistent with an expected substantial impact on the epidemic (Knight et al,).
Neonate/infant vaccine: In infants, testing for superiority of efficacy over BCG will be conducted and the magnitude of superiority should reflect the expected improvement in public health outcomes. Non-inferiority efficacy testing could be considered for an investigational vaccine offering a substantial benefit compared to BCG (eg safety in HIV exposed infants) (ref WHO PPC for New TB Vaccines). The margin of non-inferiority should infer non-inferior impact on public health outcomes.