In 2003 the European Developing Clinical Trial Partnership (EDCTP) was founded as a European Economic Interest Group by the European member states and the European Commission. When created, its target was poverty-related disease (HIV/AIDS, malaria and tuberculosis and focusing on phase II and III clinical trials). EDCTP was intended to be a platform where countries from the South and the North could receive funding and where research agendas and priorities were set jointly. The EDCTP has become a catalyst for innovative trials and successful scientific capacity development programmes filling an important gap between industry, product development partnerships (PDPs) and the bilateral North-South Partnerships between universities or research institutions.
Before releasing a conventional request for proposals, an expert consultation was held in Dublin in 2007 under the aegis of the partnership. This meeting concluded that, since the funds for clinical trials were small and the number of options limited, a brokered call would be the most efficient approach to form a consortium that could achieve more than “just another clinical trial”. The aims were multifaceted: to develop a promising product portfolio free of political/commercial constraints, to develop a network of African trial centres that would be large enough to host pivotal phase III trials, and to develop a drug development consortium that would attract future product development projects. The meeting also recognised that to ensure programme acceptance, registration was required and that such trials were expensive. Collaboration between research groups could reduce the cost of trial monitoring, training and capacity development and increase its quality.
The PanACEA groups met with external advisors from the Gates Foundation and the Global Alliance to agree that the most pressing trials goals were to take the moxifloxacin development programme to completion, to study the optimal dosage of rifampicin, and to take a new compound SQ 109 through its early phase clinical trials. This would provide a balanced portfolio of studies at different stages of development with which to begin the collaboration. Throughout the formation of the consortium, creating enhanced trial capacity in high burden countries to perform regulatory trials, and empowering African research groups to be able to compete internationally for research funds, were on the forefront of our thinking. A grant request was written to the EDCTP by the partners and reviewed externally in the usual way. Co-funding was achieved through generous grants from the participating European Union member states, the European Commission, Gates Foundation, the Global Alliance, and pharmaceutical companies, which added up to a grant of 27 million euro. The PanACEA consortium was born!
In the first funding period PanACEA has built new clinical trial capacity in three Tanzanian sites, has expanded TB expertise in Gabon and Uganda and conducted four phase II and one phase III fully GCP compliant, regulatory-standard TB clinical trials. REMox was a phase III trial design evaluating Moxifloxacin in Tuberculosis. Among the phase II trials are SQ109, a phase IIA safety study with a novel agent. HR1, a phase IIA design that rapidly evaluated high-dose Rifampicine and other Rifamycins. HR2, a phase IIB study rapidly evaluating high-dose Rifampicine and other Rifamycins. And finally MAMS-TB, a phase IIB multiple arm, multiple stage trial to evaluate four treatment regimes including SQ109, two increased doses of rifampicin and moxifloxacin.
Out of the success, harmonious collaboration, and synergy of PanACEA I, PanACEA II was established. The consortium partners successfully applied for EDCTP’s Research and Innovation Action call (RIA), and were awarded their second EDCTP grant worth almost € 11.4 million, which was supplemented with contributions by the German and Swiss government to the amounts of almost 3 million euro and 336.000 euro, respectively. The consortium was extended with PANBIOME partners from Malawi and Mozambique.
The PanACEA II programme aims to develop at least two promising TB-treatment regimens with sound prediction data for a successful phase III evaluation, and advance one new agent into phase IIB. It will take full advantage of state of the art technologies, including innovative trial designs, new microbiological markers of treatment response, pharmacokinetic-pharmacodynamic analyses and modelling techniques. As a result, drug development processes could be accelerated by several years. PanACEA II trial activities will be conducted at 11 research sites in six countries (Gabon, Malawi, Mozambique, South Africa, Tanzania, and Uganda) in sub-Saharan Africa with integrated research capacity development.
The key objectives of the PanACEA II programme are:
- To optimise the dose of rifampicin. Using the methodology developed in earlier trials, the dose study of rifampicin will be continued to evaluate 50 mg/kg rifampicin. Safety, tolerability, pharmacokinetics and extended early bactericidal activity will be assessed with strict safety stopping rules.
- To assess the safety and efficacy of two compounds: Q203 which is ready for Phase II clinical evaluation and BTZ043 which is expected to enter the clinical phase later in the programme. These compounds with novel mechanisms of activity will be evaluated through an innovative phase study design, ‘14+14’ phase IIA SMART (Sequential, Multiple Assignment, Randomized Trial).
- To evaluate several combinations of the optimal doses of rifampicin, Q203, and an optimised dose of pyrazinamide of 40 mg/kg complemented by isoniazid and ethambutol. This six-arm study will use the novel STEP design (the Phase IIC Selection Trial with Extended Post-treatment follow-up). This design closes the gap between Phase II and Phase III studies, and will predict the success rate of the new regimens in a future phase III study. The study will include an arm containing Q203 with a novel backbone, which has the potential to be a universal regimen for both drug-sensitive and drug-resistant TB.