The Plasmodium parasite continues to show a remarkable ability to develop resistance to new agents, despite efforts to find ways to minimize the risk 7. The development and adoption of ACT (artemisinin-containing combination treatment) as first-line therapy for acute cases has been a major step forward in combating this problem 8. It has also highlighted the potential utility of future new combinations that contain two or three complementary drugs with different modes of action (with or without an artemisinin component). Recent concerns in Cambodia about the loss of efficacy of artemisinins underlines the ability of the parasite to respond to new agents 9. It also shows that the global malaria community cannot afford to assume that once it has a highly effective tool (such as ACT) this will reduce the need for new drugs with novel mechanisms of action to meet future (if not yet identified) resistance problems.

There is also the need to recognize that the problem of resistance is not only restricted to Plasmodium falciparum, as illustrated by the recent identification of evolving resistance of Plasmodium vivax to both chloroquine and primaquine 10. There is a need to increase the priority of finding new drugs to tackle these problems if vivax as well as falciparum malaria is to be controlled and eliminated.

As malaria control and elimination programmes become more extensive and sophisticated, the profiles of the drugs needed for these programmes will change. As the community develops more integrated ways of delivering drugs treatment, the profiles of the drug combinations to be used in these systems have to adapt to the needs of these programmes. For example, the opportunities to deliver IPT (intermittent preventive treatment) alongside other interventions like childhood vaccination, school-age de-worming, maternal prenatal clinic visits, or bed net distributions, lead to an unmet need for new drug combinations that can be delivered in a single treatment (also possibly directly observed). Similarly, as the priority of treating the dormant liver stages of vivax malaria increases in malaria programmes outside sub-Saharan Africa, the profile of primaquine has been shown to be unsuitable and the need for a drug with a shorter dosage regimen increases 11. The Medicines for Malaria Venture (MMV) and others are working to ensure that the malaria community has up-to-date and generally agreed target product profiles (TPPs) available to work towards 1213.

Until quite recently, the focus of the global drive to control malaria has been on Plasmodium falciparum. This is understandable. Falciparum malaria is the major killer globally, notably of children and pregnant women, and it is the species that has given the most problems from the development of resistance. Now that global efforts against malaria are beginning to move beyond control to elimination, more emphasis has to be placed on Plasmodium vivax infections and developing agents that can be used against this species, especially in areas of mixed vivax and falciparum infections. Where elimination can be considered, then the removal of asymptomatic reservoirs of infection must also be considered. New agents that can be used in mass drug administration campaigns or other approaches are needed. All these changes in the objectives of delivering anti-malarial drug therapy underline the need for a continuing high level of investment in new drug R&D.

Another risk that must be recognized, as the control of Plasmodium falciparum and Plasmodium vivax improves, is the increase in importance of Plasmodium species that are currently seen as minor problems. The removal of falciparum and vivax may open up environmental gaps into which other species can enter. This will increase the need for drugs that are highly effective against other malarial species, for example Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. It is not currently clear if drugs with modes of action effective against vivax or falciparum will be adequately effective against these species once the competitive pressure of the major parasite species is removed.

The Consortium consists of nine participating institutions involved in anti-malarial drug discovery (see Table 1). The PIs representing each institutions form the Consortium Management Committee. The Management Committee is responsible for setting the workplan, identifying the priority challenges for in-depth analysis and recommendations, and overseeing the development of the outputs and proposals to the global community.

The composition of the Consortium is drawn from European and African based institutions. In order to avoid taking too parochial view of the challenges confronting anti-malarial drug discovery or unduly focusing on their particular research priorities, the work of the Consortium is also subject to external review by an Expert Advisory Group (EAG). The EAG consists of key global opinion leaders in the field of anti-malarial drug discovery and development who are able to comment on the CRIMALDDI proposals both from the R&D and policy-makers' perspective. Its terms of reference are designed to ensure that the methodology and the recommendations of the Consortium are aligned with discussions by other similar agenda-setting initiatives and do not take too Eurocentric a view of the challenges. It enables the Consortium to co-ordinate its findings with other groups (especially MalERA). At its first meeting, the Management Committee of the Consortium identified the areas of expertise that it felt should be included in the EAG. It then identified appropriate experts to be invited who met these requirements and who would bring a wider geographical perspective to the Consortium's thinking. The EAG has met once and there are plans to meet twice in 2010.

The basic approach of the project in arriving at its recommendations for the malaria community's consideration is to bring together global experts in a series of one- or two-day workshops. The starting point of each workshop is a detailed question that the participants can refine and then will use to develop interactively a set of detailed and action oriented recommendations designed to answer the question. One of the objectives of the Consortium is to try to bring new thinking from other fields of drug discovery to address the challenges that have been identified. It is hoped that the workshops will be able to find lessons from related fields (e.g. liver immunology in cancer, stem cell research, other infectious diseases) that may offer new insights worth pursuing in addressing the more intractable challenges found in malaria.

The overall process for the work of the Consortium is shown in Figure 1. The Consortium Management Committee has already met twice to identify the priority areas of focus for the Consortium (workstreams). The first meeting attempted to establish both the range of drug discovery and platform technology work required to meet the evolving needs for new anti-malarial drugs and the actual work being undertaken around the world. This then allowed the team to carry out a detailed gap analysis. At its second meeting, the team then grouped the gaps into logical workstreams, which could be possible topics for the focused workshops planned for 2010. The various workshop topics were then prioritized based on their importance to increasing the productivity of drug discovery and the degree of unmet need the Committee felt existed and the top five selected for further work (Table 2). Other topics considered are listed in Table 3. The rationale for addressing only the top five issues at this stage is presented. All this work was then subjected to review by the EAG before being taken further.

The thinking of the Consortium members (endorsed by the EAG) in arriving at these five workshop topics can be summarized as follows:-

Workshop 1 ("P. falciparum and P. vivax novel targets and classes"): despite efforts to identify novel targets and chemotypes, much anti-malarial drug discovery is still focused on a few well-established and well-characterized groups (e.g. anti-folates, DHODH) and primarily on the blood stage of the parasite's life cycle. Are there ways to accelerate the identification of novel targets and drug classes that act elsewhere?

Workshop 2 ("Managing the wealth of new HTS data"): various research groups and pharmaceutical companies are placing data on large numbers of positive hits from whole cell malaria parasite high throughput screening into the public domain. However, there is a risk that there may not be adequate systems in place to allow this data to be turned by interested groups into meaningful information to support drug discovery. Are there one or more approaches to making this data available that will make it more useful and user-friendly to the wider malaria community?

Workshop 3 ("Artemisinin resistance"): since the identification of resistance to artemisinins in Cambodia, most of the research work on this topic has been focused on finding ways to prevent its spread outside the limited area where it is currently found. However, it is still unclear what the exact mechanism of this resistance is and the degree to which it may cause resistance to newer peroxide drug candidates. Is it possible to design an integrated research programme that will not only identify the mechanism of the resistance, but be able to be predictive of cross-resistance and also allow strategies to be developed to minimize its spread and preserve existing artemisinin-containing drugs?

Workshop 4 ("Stage-specific screening methods"): one of the barriers to anti-malarial drug discovery is the lack of robust screening methods that can be replicated by laboratories across the world. It is not possible to screen properly against all species of the human malaria parasite, or for activity against stages of the life cycle other than Plasmodium falciparum blood stage. Is it possible to develop recommendations on the priorities for research into new screens that are stage specific and can reliably identify species other than P. falciparum?

Workshop 5 ("Using chemistry to understand biology"): there is a large amount of information now available on the chemical structures that show activity against Plasmodium in whole cell screens. It ought to be possible to use information on the chemical structures that show activity to draw conclusions on the underlying parasite biology that is being targeted. What would a research programme to identify the biological processes that are being interrupted by the active chemotypes look like and what would need to be in place to support such a programme?

The next stage of the process will be to hold workshops to design detailed and action-oriented work plans to address the key issues identified. These workshops will be one or two days in duration. The Consortium will invite 10 to 20 global experts in the particular field of the question, but it will aim not to draw solely on experts from within the malaria community. Efforts will be made to bring in outside expertise that can bring new thinking on existing problems (e.g. what can be learned on issues of resistance from the anti-bacterial and anti-viral world). The selection of participants for the workshops is being made by the Workshop Leaders in consultation with the rest of the Management Committee and the EAG. They will attempt to identify global experts with the key skill sets and expertise to address in depth the topic of each Workshop. These workshops will be facilitated in order to ensure maximum interactivity and to keep the meeting focused on the specific question identified for analysis. The detailed questions to be addressed at the five priority workshops are shown in Table 2. If the workshops alone are not enough to develop adequate recommendations to the satisfaction of the participants, then consideration will be made to having additional meetings or other forms of collaborative discussions to enable quality answers to the workshop questions to be agreed upon. The outputs from the workshops will then be consolidated with the help of the EAG for publication at the end of the project. This will allow the recommendations to be available to the malaria community as one input to the agenda setting mentioned earlier in this paper.

The CRIMALDDI Consortium is aware of the need to align and coordinate its efforts with those of other related initiatives, most notably the Global Malaria Action Plan and MalERA. The presence of MMV and TDR as Consortium members is intended to ensure good coordination with existing efforts. The Chair of the Drug Discovery Workstream of MalERA is a member of the EAG. Members of the Consortium have also participated in meetings of the MalERA Drugs Consultative Group. As mentioned elsewhere, MalERA's focus is broad, high-level, and medium to long-term. CRIMALDDI's focus is on a few key priority areas where it plans to go in depth into their needs and where the impact can be seen in the next decade. Therefore the two initiatives are complementary.

The Consortium is well aware that it must try to gather input from as wide a range of stakeholders as possible. Formally it can rely on input from the members of the Consortium, the EAG, and the participants in the five workshops. They represent not only five European and two African leading drug discovery research centres in the Consortium. They also include key international organizations (TDR), funders (e.g. Bill and Melinda Gates Foundation, Wellcome Trust, MMV), major institutions (e.g. London School of Hygiene and Tropical Medicine, Institut Pasteur, Columbia University, Swiss Tropical and Public Health Institute), and the pharmaceutical industry. The geographical reach of the input covers not only European and African based institutions and organizations, but also ones based in India, South East Asia, and North America.

However the Management Committee decided at its first meeting that it needed to try to gather as wide range of input as possible from the anti-malarial community. To this end it has set up a website 17 where anyone will be able to view the outputs of the work to-date and to comment both on the outputs and on specific questions posed by the Consortium through the site's discussion forum. The members of the Consortium have and will continue to take every opportunity to raise the awareness of its work at relevant meetings (e.g. MIM Conference in Nairobi, November 2009).

The website will include detailed summaries of the work concluded to-date as well as the plans for the next steps. Minutes of the EAG will also be posted. In addition, the Consortium will publish summaries of the conclusion of the workstreams as they become available. Key issues that are raised at the workshops will be placed into the discussion section of the website so that non-participants in the workshops will have an opportunity to make their own comments. These will be taken into consideration when the final recommendations are written up. The Consortium plans to present its overall conclusions and recommendations at a major conference in late 2010 or early 2011.