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the development of new and affordable drugs12,17,18. The few existing drugs often fail due to the emergence of resistance, have sig- nificant compliance and safety issues, or are inaccessible due to lack of affordability and/or appropriate infrastructure19,20,21,22. The need to undertake appropriate drug R&D to redress this situation is massive (TABLE 1). Moreover, because of the timing of industry disengagement, research into tropical diseases has missed out on the substantial advances in drug discovery technology brought about by the developments in mole- cular and structural biology, medicinal chemistry and robotics in the 1980s and 1990s. With the availability of several para- site genomes and the focus on PPPs, the full strength of modern drug discovery research is only now beginning to be applied to neglected diseases.

The creation of the United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO/TDR) in 1975 (REFS 23,24) enabled a partnership-oriented approach to drug discov- ery and development between public-sector organizations and private companies to be established. This process has rapidly acceler- ated since the late 1990s, for example, through the creation of the Medicines for Malaria Venture (MMV)24,25,26 and other organiza- tions, which are now called PPPs12,27,28. These organizations have increasingly structured themselves in line with industry management practices in the expectation of being able to deliver new products and new development candidates. A recent increase in funding opportunities through national governments and philanthropic institutions such as the Rockefeller and Gates Foundations has fuelled their work and allowed projects to be initiated with million-dollar budgets. The goals, strategies and achievements of some PPPs involved in drug development for neglected diseases are provided in BOXES 1 and 2. With the exception of WHO/TDR, the PPPs listed are barely five years old and most of the achievements are based on the outcomes of intermediate success indicators.

Most PPP regulatory successes to date have been based on the identification and screening of available compounds from other indication areas, followed by clinical develop- ment (BOXES 1 and 2). However, building on the example set by the biotech industry29, innovative discovery-phase partnerships are also becoming viable within PPPs, most notably at MMV30,31 and at the Global Alliance for Tuberculosis Drug Development (GATB). Before the biotech era, drug discovery

In this article, we discuss the challenges, recent developments and new thinking on drug R&D for neglected diseases through public–private partnerships. The focus on virtual drug discovery and development as operationalized through these partnerships brings many advantages, as well as scientific and managerial challenges. Some are common to those faced by all drug R&D ventures. Others, for example the need for drugs with a very low cost of manufacture that are easy to use in resource-poor environments and an active engagement in disease-endemic countries, are unique to this novel paradigm.

Drug R&D is technologically challenging, capital intensive and largely driven by market incentives. Although the market system has generated many innovative therapies, it can- not cater for diseases for which commercial incentives are insufficient to trigger private sector investments in R&D1,2. In the devel- oped world, such diseases are referred to as ‘orphan’ diseases and affect small numbers of patients3. In less developed countries, many diseases can affect millions of patients, but their lack of ability to pay for market-financed innovative products means there is still no market for drug developers to exploit4,5. The common term for these diseases is ‘neglected diseases’, but they are often referred to as tropical diseases, endemic diseases, diseases of the poor or orphan diseases6,7,8. They include diseases such as malaria, tuberculosis, African trypanosomiasis (sleeping sickness), Chagas disease, dengue, leishmaniasis, schistosomiasis, onchocerciasis and lymphatic filariasis9,10,11. Additional factors that further depress the market for innovative new drugs for these diseases include poor regulatory infrastruc- ture in many countries and competing coun- terfeit drugs2,12,13. The net effect is that only 10% of global R&D resources are directed at diseases accounting for 90% of the global disease burden7,14,15.

Reducing the burden posed by neglected diseases requires increased R&D for new

drugs, vaccines and diagnostics4,5,15. A consoli- dated public–private and philanthropic approach that stimulates R&D for these dis- eases can compensate for market failure by reducing the costs and risks involved for both public- and private-sector partners. This works through the public- and philanthropic- sector provision of funds that complements private-sector resources. This partnership approach, operated through a virtual R&D methodology, brings many advantages, including a broad choice of projects, partners and manpower, as well as flexibility and a reduced need for capital investment. Set against a backdrop of the differing cultures of the public and private sectors, there are also many unique management and organizational challenges associated with these partnerships.

It is important to recognize that the gover- nance systems put in place for public–private partnership (PPP) organizations are key to directing these activities. This element is particularly important when one considers the policy debate underway relating to intel- lectual property rights, innovation and access to essential medicines12,15,16. However, this review focuses not on governance, but on the executive, scientific and functional aspects of managing partnerships for neglected disease drug R&D.

The evolution of PPPs The public sector has long taken an interest in stimulating the discovery, development and availability of new drugs. But with the possible exception of a few public sector institutions, such as the Walter Reed US Army Institute of Research (WRAIR) and the Central Drug Research Institute (CDRI) in Lucknow, India, they have not focused on establishing their own drug development infrastructure. The pharmaceutical industry, during the past 50 years, has developed expertise in medicinal chemistry and other technologies for the con- version of basic scientific discoveries into new therapies. However, the disengagement of most pharmaceutical companies from tropical disease R&D in the 1970s left a huge gap in

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Virtual drug discovery and development for neglected diseases through public–private partnerships Solomon Nwaka and Robert G. Ridley

S C I E N C E & S O C I E T Y

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Initiative that includes dedicated drug dis- covery laboratories in Madrid, Spain. Novartis has recently established the Novartis Institute for Tropical Diseases in Singapore. These industrial centres will have a major impact in the coming years. For the purposes of this article, however, we will focus on activities directed through the types of partnership listed in BOXES 1 and 2.

Though the number of pharma compa- nies engaging in PPP is encouraging, it should be mentioned that with increasing market pressures, the past few years have witnessed the exit of several major pharmaceutical com- panies from broad-based anti-infective R&D activities, most notably with respect to the development of antibacterials. There is a fear that with increasing resistance to antibacterials, and increasingly stringent demands from regulatory agencies, a huge gap could arise in the antibiotic market in the coming years32. Perhaps the virtual PPP management approach might ultimately prove useful for other global infectious diseases.

Management of virtual drug R&D The goal of the organizations listed in BOXES 1 and 2 is to bring to patients in developing countries drugs that meet unmet medical needs, and which are appropriate and afford- able12,15,30. This calls for a product-focused approach, for which the required mindset, until recently, was only found in the pharma- ceutical industry. It also requires recognition of the complexity of the drug R&D process, as illustrated in BOX 3.

Many issues associated with PPP drug R&D are common to all drug R&D, and many of the management approaches are taken from best practice in industry. FIGURE 1 indicates the major stages involved in the 10–15 year process of drug discovery and development. It also highlights the manage- ment differences and style required at the discovery and development stages, the over- lap of tasks between industry and academia in a partnership-managed process, and based on MMV calculations for competi- tively selected malaria projects, the probability of moving from one stage to the other through the process31. As for all R&D pro- jects, the liabilities associated with existing drugs need to be understood and addressed through clearly defined product profiles. Major objectives in terms of milestones and timelines need to be set, and a rigorous and regular review of progress needs to be established, especially at key decision points. Further- more, there is a need to continually evaluate individual projects against the overall needs and situation of the global R&D portfolio.

developing R&D partnerships based on ven- ture capital investment27, stimulated the development of the PPP virtual model in the 1990s.

It is also worth noting that the increase in organizations promoting R&D for neglected diseases through PPP activity has been com- plemented by some important industry initia- tives. For example, AstraZeneca has established a strong drug discovery effort for tuberculosis based at their laboratories in Bangalore, India. Similarly, Sanofi has established a malaria initiative. GlaxoSmithKline has estab- lished Diseases of the Developing World

and development was performed mainly by units within integrated multinational pharma companies, but the development of biotech has encouraged specialization according to stages in the R&D cycle of drug products29. This has provided a lot of flexi- bility within the industry, as pharma com- panies have increasingly sought deals with others to co-develop products and/or com- mercialize them. The fact that fully inte- grated pharmaceutical companies seek and contract with partners with specific R&D expertise, even for such activities as lead optimization, coupled with the concept of

Table 1 | Limitations and desired product profiles of drugs for tropical diseases

Drugs Limitations Desired profile of new products

Malaria

Quinine Compliance, resistance, safety Overcome resistance; oral, with Chloroquine Resistance option for parenteral use for Primaquine Safety patients in coma; use in small Sulphadoxine- Resistance children; use in pregnancy; cure pyrimethamine in three days; inexpensive. Amodiaquine Resistance, (safety) Artemisinins Compliance, cost

(Good Manufacturing Practice) Mefloquine Resistance, cost, (safety) Halofantrine Resistance, cost, safety Co-artemether Compliance, cost, resistance potential Malarone Cost, resistance potential

Tuberculosis

Combinations of: Isoniazid Length of treatment (six months), Use in combination with standard Pyrazinamide compliance, resistance products; oral; reduce Ethambutol treatment time to four months; Streptomycin overcome resistance Rifampicin

African trypanosomiasis

Suramin Efficacy, injectable Use against early and late stage Melarsoprol Safety, injectable disease; active against both Pentamidine Resistance, compliance, injectable major species; parenteral with Eflornithine Cost, injectable option for oral use; cure in less

than 14 days; inexpensive.

Leishmaniasis

Antimonials Safety, injectable, resistance Overcome resistance; oral drug Pentamidine Safety, injectable, resistance or safe injectable; cure in less Amphotericin B Safety, injectable than 28 days; inexpensive. Liposomal Cost, injectable amphotericin B

Chagas disease

Benznidazole Activity limited to acute stage of disease, Active against blood and tissue some safety issues forms of parasite; active in

Nifurtimox Activity limited to acute stage of disease, prevention of chronic stage of some safety issues disease; inexpensive

Schistosomiasis

Praziquantel Decreasing efficacy observed (resistance?) Active against adult worms; high Oxamniquine Multiple dosing required efficacy; oral; single dose

preferred; inexpensive.

Onchocerciasis

Diethyl- Safety Oral; macrofilaricide that kills carbamazine adult worms and allows cure; Ivermectin Requires regular preventive administration also active against microfilariae.

to kill young worms. Does not kill adult worms (not a macrofilaricide).

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competitors. Other important issues covered by the agreements include balancing the need for protection of information with the desire of academic investigators to publish, and issues relating to clinical trial liability.

Virtual drug development. With the increasing complexity of regulatory requirements and guidelines that have come into force since the 1960s, industry has improved its methods for coordinating and managing drug develop- ment projects. Central to this process is the concept of a product development team. Core contributors meet regularly to discuss strategic issues, submit themselves to common man- agement and commit to delivering specific pieces of work within given timelines that facilitate an integrated development plan.

This concept has now been put into oper- ation and tested in several PPP projects with some regulatory success, most notably by WHO/TDR33. Teams consisting of pharma company experts, WHO/TDR experts, clinical investigators and other external experts are charged with the overall development pro- gramme, including timelines, budget, study design and protocols, which need to comply with good clinical practices. This model worked recently for the development, with Zentaris AG, of miltefosine, the first ever oral drug for the treatment of visceral leish- maniasis34 and for the development of

A more flexible management approach is required at the exploratory and discovery stages of the process than at the develop- ment stage. It should be noted that moving a project from discovery into development requires meeting a rigorous set of criteria (BOX 4), as well as strong management and organizational skills. This is even more challenging under the multiple partnership approach in which several parties need to be comfortable with choice of the final com- pound and, in some cases, with the selection of a new development partner.

We now discuss some of the key elements relating to how partnerships can manage virtual drug development and discovery. The pre-drug discovery and the post-drug regis- tration interfaces will also be discussed, as they are particularly important for neglected diseases and deserve the attention of those engaged in PPP activities.

Selection and review of projects. In pharma companies, despite the use of external consul- tants, internal senior management has the major responsibility for decisions relating to the selection and review of projects. For PPPs, scientific advisory committees consisting of external experts from both academia and the private sector are given a more powerful role, which includes support on project selection and funding, project review and recommen- dation of project termination. This enables a full range of expertise to feed into deci- sions and reassures collaborators that the decisions are fair and unbiased. Most organi- zations also borrow the concept of traditional science funding agencies and issue a ‘call for proposals’ from which to select projects.

One innovation in the use of external committees, pioneered by MMV, has been to utilize the industry practice of project leaders defending their projects ‘face-to-face’ with the scientific advisory committee. This has the advantage of generating a true dialogue between researchers and managers on the value of the project and allows for a more transparent discussion of issues.

Negotiating partnership agreements. As part- nerships involve millions of dollars and com- mit organizations to work together over several years, legal agreements are required, just as in a business environment. The agree- ment describes the objectives of the research, how the project will be managed and defines the obligations of each party. Crucially, it also defines how intellectual property rights should be used by the parties, and the rights of each party to the outputs of the project. These intellectual property issues, as well as

management of the project, are at the heart of crafting a win–win agreement required to attract and retain partners, especially indus- trial partners. The public sector, through rights obtained in the agreement, requires a commitment from the commercial partner, with respect to both manufacturing and pro- viding preferential pricing of products for developing countries, particularly in the public sector. It also requires the right to a license to continue the project (with another partner) if, for some reason, the company terminates involvement. In the case that a profitable drug results from the partnership, a royalty might also be negotiated by the public-sector partner to be re-channelled into R&D efforts.

PPP agreements must be structured to balance the risks/benefits for all parties, including the contributions from each partner. Small pharma companies wish to ensure that they are able to work to suitable profit margins if the drug is successful. Large pharma com- panies might be less concerned about the profit of these drugs, given their low market value, but they do want to ensure that they break even or at least minimize their costs. Both types of pharma company also want agreements that protect their intellectual property. They are happy for such intellec- tual property to be utilized within the services of the project, but they wish to limit any prospect of it somehow becoming available to

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Box 1 | Organizations managing public–private partnership drug R&D

Management of projects within a large organization United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO/TDR)

• Type of organization: Special Programme created 1975 following World Health Assembly Resolution. Co-sponsored by the United Nations Development Programme, the World Bank, the WHO and managed through the WHO as its executing agency. Funded mainly through international, government and philanthropic foundation contributions.

• Goals/mission: Develop new tools and methodologies for control of ten target diseases (includes drugs, but not exclusively focused on drugs). Strengthen research capabilities in disease-endemic countries.

• Strategy: Chemotherapy Portfolio Review Committee selects and annually reviews activities in drug R&D area. Coordinated screening to facilitate drug discovery against a full range of target organisms, both in cell culture and in animal models, with a centralized database. Product Development Teams established to manage drug development projects’ potential to establish drug discovery teams.

• Accomplishments in drug R&D: Examples of registrations include praziquantel with Bayer for schistosomiasis (1980); ivermectin with Merck for onchocerciasis (1987); eflornithine with Marion-Merrrill Dow for African trypanosomiasis (1991); liposomal amphotericin B with NeXstar for visceral leishmaniasis (1994); injectable artemether with Rhone-Poulenc Rorer for severe malaria (1997); injectable β-arteether with Artecef for severe malaria (2000); miltefosine with Zentaris for visceral leishmaniasis (2002); and chlorproguanil-dapsone with GlaxoSmithKline for malaria (2003).

Current development portfolio consists of seven projects spread across several diseases. Several discovery and development projects also under discussion. Strong promotion of Good Laboratory Practice, Good Clinical Practice and bioethics through projects.

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contract research organizations to help manage the process of development, to facil- itate sharing of information within the team and to undertake dossier assembly. The appropriate regulatory strategies for products targeting neglected diseases in developing countries is a topic that is receiving wide- spread attention and debate.

Virtual drug discovery. Extending the product development team concept to drug discovery is logical, but creates a unique set of chal- lenges. Virtual drug discovery does not occur to the same degree within industry as does drug development. Much of virtual drug development is built on sourcing and com- missioning discrete packages of work that ultimately combine to form the dossier. Virtual drug discovery, however, especially in the early stages, requires a far more continu- ous, interactive exchange of ideas between scientists from a broad range of disciplines within an established research team.

MMV was the first organization to put the theory of PPP-driven virtual drug dis- covery into practice in a concerted manner, and has initiated several virtual drug discovery projects25,31,37. MMV achieved a notable success following a three-year lead-optimization project based on an antimalarial peroxide. A virtual team consisting of chemists in Nebraska, USA, pharmacokineticists in Melbourne, Australia, and parasitologists in Basel, Switzerland, who were linked to Hoffmann-La Roche for overall guidance and toxicology expertise, have recently submitted a candidate antimalarial for preclinical devel- opment31,38. The compound has been licensed to Ranbaxy, which will be co-developing the product with MMV.

Numerous lessons have been learned in this process. A strong team spirit and com- mitment are paramount when teams are operating at such distances. Frequent e-mail and teleconferencing, supplemented with regular face-to-face meetings and rigorous project team review, is also important. Project review at MMV consisted of quar- terly reports and a major annual report, combined with a face-to-face presentation to the scientific advisory committee. As the project neared its objective of clinical candi- date selection, there was greater coordina- tion of activities and more assertive central project management. The early establish- ment of a product profile and its continued detailed refinement (BOX 4) was essential to the team’s success.

Virtual drug discovery involving several academic and industrial partners on this scale is new and seems to be showing strong

pharmaceutical company partner might lack the necessary infrastructure to cover regula- tory aspects. In other projects, such as those for African trypanosomiasis, there might be a need for the public-sector organization to take them forward into early clinical studies without a pharmaceutical company partner. In these cases, there is growing utilization of

chlorproguanil-dapsone with GlaxoSmith- Kline for the treatment of malaria35,36.

This model is evolving as it is being adapted to more projects, notably within the GATB, Drugs for Neglected Diseases Initiative (DNDi) and the Institute for One World Health (IOWH), as well as TDR and MMV (see BOXES 1 and 2). In some cases, a small

Box 2 | Organizations managing public–private partnership drug R&D

Management of projects within small organizations Medicines for Malaria Venture (MMV)

• Type of organization: Not-for-profit foundation established in Geneva under Swiss law. Legally established in 1999 following initiation and incubation for two years in WHO/TDR. Funded mainly through international, government and philanthropic foundation contributions.

• Goals/mission: Discover, develop and deliver one new antimalarial drug every five years through public–private partnership.

• Strategy: Expert scientific advisory committee supports internal managers in the selection and review of projects. Product development teams manage development projects. Strong emphasis on virtual research teams also managing discovery projects.

• Accomplishments in drug R&D: Strong portfolio established with 21 projects at different R&D phases. Ten projects in development. First discovery project (synthetic peroxide) successfully made the transition into development. First registrations envisaged for the end of 2006.

Global Alliance for Tuberculosis Drug Development (GATB)

• Type of organization: Not-for-profit foundation based in New York, with offices in Brussels and Cape Town. Legally established in 2000. Funded through government and charitable foundations.

• Goals/mission: Accelerate and ensure the development of new, faster-acting and affordable tuberculosis medicine.

• Strategy: Selection and management of portfolio of drug candidates with assistance of scientific advisory committee. Activities outsourced. Investment in process development and chemical infrastructure for tuberculosis drug development.

• Accomplishments in drug R&D: Portfolio established with 11 projects at different R&D phases. Three projects in development.

Drugs for Neglected Diseases Initiative (DNDi)

• Type of organization: Not-for-profit Swiss foundation based in Geneva. Legally established in 2003. Founding partners include institutions from developed and developing countries. Regional offices envisaged. Funded mainly through Medecins sans Frontières.

• Goals/mission: New drugs for most neglected diseases. Technology transfer through North–South and South–South collaborations.

• Strategy: Scientific advisory committee for selection of projects combined with proactive project establishment. Proactive management of projects.

• Accomplishments in drug R&D: Portfolio under development and some projects under discussion. Call for proposals initiated with assistance from WHO/TDR.

Institute for One World Health (IOWH)

• Type of organization: Not-for-profit pharmaceutical company, based in San Francisco. Established in 2000. Funded mainly through private sources and the Gates Foundation.

• Goals/mission: New medicines for infectious diseases that disproportionately affect the developing world.

• Strategy: Focus on licensing late stage development candidates and on drug development, rather than on drug discovery.

• Accomplishments in drug R&D: A portfolio of four development projects established in visceral leishmaniasis (with WHO/TDR), cutaneous leishmaniasis, Chagas disease and paediatric secretory diarrhoea.

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with basic science and genomics (upstream interface). These are especially important for PPP projects, as it is at these interfaces that PPPs interact most intimately with the tradi- tional public-sector organizations that invest in these diseases, whether they be science research agencies (upstream) or disease control agencies (downstream).

promise for neglected diseases. It could have broader relevance for the pharmaceutical industry as a whole as it seeks new para- digms to enhance its productivity. Some pharma companies are increasingly con- tracting out areas of discovery that had pre- viously been performed internally; for example, the structural determination of

protein–ligand complexes, medicinal chem- istry for lead optimization and screening.

Managing the interfaces of drug R&D There are two important pipeline interfaces that need to be managed. The first is the inter- face with post-regulatory studies (down- stream interface). The second is the interface

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Box 3 | The process of drug discovery and drug development

Drug discovery (part a) involves different stages, including: basic exploratory biology on target identification and validation; assay development; lead identification, which usually requires access to high-throughput screening; medicinal chemistry and pharmaceutical lead optimization; and drug candidate selection62–65. The significance of modern medicinal chemistry in both identifying an appropriate lead molecule and the iterative process of lead optimization is particularly poorly understood outside the pharmaceutical industry and needs to be continuously emphasized. Optimization for pharmaceutical properties (adsorption, distribution, metabolism and excretion (ADME)), lack of overt toxicity, as well as for efficacy against the target organism, are crucial25,67. Drug candidates fail to achieve registration for several reasons: bio- pharmaceutical properties such as oral bioavailability and formulation issues are responsible for about 39% of failures, whereas toxicity constitutes about 21%. These factors are as important as lack of efficacy, which is responsible for about 29% of failures66,67. Development processes (part b) are indicated that need to be managed once a candidate compound enters preclinical development. Process chemistry is initiated to assess the cost of goods, compound scalability, stability and safety under Good Manufacturing Practice (GMP) conditions. The compound also undergoes preclinical animal safety studies under Good Laboratory Practice (GLP) conditions68. Following a successful Investigational New Drug application, the compound can undergo its first entry into humans (Phase I). The next stage is Phase II, which focuses on determining the optimal dosing of the product, followed by a pivotal Phase III study against a comparator product48,63,69. On completion of clinical development, sponsors can submit a Marketing Authorization Application (MAA) to regulatory agencies in Europe; in the United States, the MAA is called a New Drug Application for small molecules48,70,71. To allow easy submission in the same format in major geographical regions and to significantly save time and cost, the International Conference on Harmonization reached consensus on the organization of the Common Technical Document for an MAA70,71.

a

b

Target selection Validated? Robust assay system? Structural information? Lead inhibitors?

Target Validated hits Leads Drug candidateInhibitors

More detailed potency/ efficacy studies; pharmacokinetics; early toxicology

Screen in animal models; pharmacokinetics analysis

Screen in culture

High throughput screening

Iterative medicinal chemistry Optimize efficacy and pharmaceutical qualities

Product development

Natural products/traditional medicines

Raw material, GMP production and analysis

Formulation, development and analysis

GMP production of formulated product and analysis

GMP scale up of raw material production and formulation

1 Registration Delivery/

implementation Pre-clinical Safety Studies (GLP)

Clinical Phase I

Clinical Phase II

Clinical Phase III

2 3 4 5

Mutagenicity

Detailed pharmacology

Acute toxicity

Pharmacokinetics/ADME

Sub-acute repeat dose toxicity

Supplementary animal pharmacology

Carcinogenicity

Chemistry

Pharmacy

Reproductive toxicology

D ru

g c

an d

id at

e

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the best way to translate the insights obtained from genomics into new, robust chemical leads that can form the basis of innovative drug discovery. In this regard it is notable that the genomes of a number of medically important parasites are available39,42,43; how- ever, genomics needs to link with chemistry before it can deliver drugs25,44,45. In the market- driven pharma sector, advances in genomic technologies to help rapidly identify targets, high-throughput screening, in silico model- ling and screening, and X-ray crystallography are facilitating both our understanding of infectious organisms and our competence

studies to better understand how to utilize the drug in specific high-risk groups, such as HIV-co-infected patients and pregnant women, will be initiated soon. These types of study would not occur in such a public- health-oriented way, nor would they happen so rapidly, if the development had occurred solely as a private-sector project, with market potential as the main driver.

Upstream interface. A lot has been written about the potential of genomics to revolu- tionize drug discovery39,40,41. The next big challenge in tropical diseases is determining

Downstream interface. Recent experience indicates that developing drugs in a PPP results in a more rapid transition to public- health-oriented Phase IV studies. These studies focus on better assessing and understanding a product’s use in a ‘real-life’ environment. For example, the involvement of the Indian Council for Medical Research in the develop- ment of miltefosine for visceral leishmaniasis facilitated a rapid transition to multi-country Phase IV studies to assess the drug’s potential for use in national policy. Broad public sector involvement in chlorproguanil-dapsone development for malaria means that several

Target identification and validation (basic biology/ biochemistry/functional genomics/bioinformatics), develop screening assay, X-ray crystallography

Complete assay development, HTS, identify hits, X-ray crystallography, medicinal chemistry to improve potency of hits, confirm robustness of lead

Medicinal chemistry, SAR, improve potency, in vivo testing in rodents, exploratory PK, metabolism, exploratory toxicology. Compound selection

Complete toxicology (safety studies in animals), process chemistry scale up, IND, formulation, batch manufacture

First time in humans: safety, tolerability, PK. 20–80 subjects exposed

Clinical proof of principle, dose-range finding, early side-effect profile: 200–300 subjects exposed

Large safety and efficacy studies: 1000–3000 subjects exposed

Submission of dossier to regulatory agency. Manufacturing. Post- launch trial (Phase IV)

Need to encourage focused innovation; flexible approach needed with exploratory scientists

Utilize desired product profile to dictate goals and research

Pro-active coordination and management needed as approach compound selection

Focus on scientific rationale and development plan and strategy

Rigorous attention to detailed development plan and strategy

Increased attention to regulatory guidelines and standards; attention to timelines and costs

Focus on delivery of agreed product label

Label: increased specificity and definition

Exploratory early discovery

Lead identification

Lead optimization

Preclinical transition Phase I Phase II Phase III Registration

30% success rate

65% success rate

55% success rate

55% success rate

70% success rate

50% success rate

65% success rate

95% success rate

Description of activities

Process for competitively selected projects

Management issues

Basic science Discovery RegulatoryDevelopment

Academic Industry

CRO

Figure 1 | Managerial aspects of drug R&D process. The figure focuses on partnership evolution and experience of public–private partnerships (PPPs) in key tasks performed in academia, pharma (big, small or biotech) and contract research organizations (CROs; top of figure). Success rates and managerial focus as projects progress from discovery to development are shown based on Medicines for Malaria (MMV) analysis for competitively selected malaria projects31,37. Partnerships usually begin with academia for exploratory research, and move on to partnerships involving academia and industry once there is a need for chemistry at the drug discovery phase. Especially in cases in which small pharma companies are involved, there is frequently a need to involve CROs as projects move into the development phases. Success rates vary from phase to phase, and from project to project. However, an approximate average success rate from phase to phase in infectious disease is presented on the basis of MMV analysis for malaria31,37. Some observed differences in management needs between discovery and development projects are highlighted. HTS, high-throughput screening; IND, Investigational New Drug application; PK, pharmacokinetics; SAR, structure–activity relationships.

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project might be a ‘me too’ approach; that is, an attempt to get an improved drug from an existing class. An example of this is a project funded by the Gates Foundation at the University of North Carolina, USA, to develop improved orally bioavailable diamidines against African trypanosomiasis54. A medium- risk project might be to ‘piggy back’ on existing chemistry designed against a target of relevance for human disease that also has rele- vance for a tropical disease indication. For example, farnesyl transferases have been iden- tified as potential targets for malaria and African trypanosomiasis, and projects have started taking advantage of medicinal chem- istry on human farnesyl transferase inhibitors for cancer55. Similarly, cysteine proteinases have been identified as targets for malaria and Chagas disease, and projects have been initi- ated that are based on inhibitors of human cathepsin K56. The highest-risk and perhaps most challenging projects are those that try and derive a new class of inhibitor against a new molecular target. There are, as yet, no examples of such compounds entering clinical

at rational drug design, as well as increas- ingly supporting an early industrial R&D pipeline41,42,46. However, these technologies need to be better applied to tropical diseases if the pipeline for drug discovery and develop- ment is to remain full and healthy. With the increased availability of non-proprietary chemical libraries and the increasing ease with which high-throughput screening can be set up, this is a challenge that science-funding agencies and academic organizations can increasingly address.

Portfolio strategy Portfolio modelling is useful for product R&D organizations, as it helps to determine an optimal number of projects to be established at different stages of discovery and develop- ment, taking into account issues such as risk, cost and novelty. The high attrition rate for new chemical entities is well established and is largely responsible for the high cost of bringing drugs to market. Most drug candidates fail before they reach the clinic, and only one in every five drugs that enter clinical trials reaches the market. If the costs of compounds that do not make it to the market are consid- ered, the cost of development is calculated to be in the range of US $0.5–1 billion44,47,48,72. The portfolio approach to product R&D, in which multiple projects are supported, spreads the risk of investment and thereby reduces dependence on a single compound or project for success. The administration of a portfolio of projects offers advantages both scientifically and administratively.

Issues addressed through portfolio manage- ment. The large number of unmet medical needs illustrated in TABLE 1 demonstrates that several products and projects are needed across a range of diseases and within specific diseases to make an impact. There are a number of ways in which such portfolios can be built up.

Early successes can often be achieved with compounds that already have extensive clinical or veterinary experience and which can be applied to a new indication. TDR has achieved some notable successes with this strategy. For example, ivermectin, originally developed by Merck for dog heartworm, was developed for human onchocerciasis49. Eflornithine and miltefosine were originally developed for cancer and later developed for African trypanosomiasis and visceral leish- maniasis, respectively34,50,51,52. Paromomycin, originally developed for oral use against gut pathogens, is now in Phase III trials spon- sored by TDR and IOWH as an injectable for use in visceral leishmaniasis.

Short-term solutions need to be matched by long-term, innovative, high-risk discovery projects. The MMV partnership portfolio so far offers the strongest example of this approach25,31,37. In the case of malaria, the immediate problem is drug resistance. This is being countered in the short term (two to four years) by developing fixed-dose combi- nations of existing drugs with the expectation that efficacy will be improved and resistance development slowed down31,53. In the medium term (five to seven years) new molecules are being developed that belong to known classes of drug. They will be an improvement on current drugs, but it might be that resistance will develop relatively rapidly. These projects are complemented by long-term (more than ten years) drug discovery projects to generate new classes of antimalarials. As these new drugs will be purpose synthesized, improve- ments in pharmacokinetic and safety issues can be built into their design in addition to improved efficacy.

Within drug discovery projects there is also a hierarchy of project risk. A low-risk

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Box 4 | Information required prior to candidate selection

Therapeutic profile: compound must have a strong chance of meeting target profile in terms of efficacy, safety, route of administration and treatment regimen.

Efficacy data (in vitro and in vivo activity) • Enzyme activity: IC

50 /K

i and selectivity against enzyme/receptor/target.

• Whole organism activity: IC 50

/IC 90

versus laboratory strains (sensitive, resistant), comparison against standard drugs, interactions with existing agents, mechanism of action (cidal or static).

• Animal models: ED 50

/ED 90

with appropriate formulations. Parenteral and oral activity. Other more detailed animal testing as appropriate. Postulate curative dosing regimen.

Metabolism • In vitro metabolism: rate with mouse, rat, dog and human microsomes, major metabolite iden-

tification. Drug–drug interaction potential. Absorption potential (for example, CACO-2 cells).

• In vivo pharmacokinetics: po/iv pharmacokinetics in rodent species over therapeutic dose range. Plasma half-life, C

max , clearance and volume of distribution in rodent. Oral

bioavailability in rodent. Major circulating/active metabolites. Human dose-range projection.

Safety • In vitro selectivity: broad toxicity-related receptor/enzyme profiling. Cytotoxicity.

• In vitro mutagenicity: structural alerts (for example, DEREK). Ames test (micronucleus test if Ames is positive).

• In vitro cardiac: hERG binding (dog Purkinje fibre test if hERG is positive).

• Animal toxicology: Exploratory single-dose and multiple-dose range finding to demonstrate lack of overt toxicology concerns in major organs.

Chemistry • Physical form: compound characterized (log D, pKa, solubility, stability). Preliminary

analytical method developed. Salt form decided. Preliminary formulation.

• Manufacture related: economic scale-up assessed. Preliminary cost of good estimate.

• Back-up strategy.

• Objectives: potential shortcomings of candidate identified. Potential and time frame for improvement assessed.

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testing against parasites might be utilized as a resource for several projects. Clinical investi- gators might be utilized for numerous pro- jects. Similarly, a small group of preferred contract suppliers might be used for out- sourced preclinical work or regulatory sup- port. An interesting concept was recently initiated by MMV and the GlaxoSmithKline Diseases of the Developing World pro- gramme. A ‘mini-portfolio’ of projects has been established under a single legal contract, thereby allowing more flexible allocation of resources and technologies across projects57.

In summary, the huge gap that exists today in product R&D for tropical diseases justifies investment in a balanced portfolio of both short- and long-term projects. Investing in the improvement or development of existing agents brings short-term impact, but contin- uous investment in innovation to identify

in a given university; access to a specific class of compounds at a company). By bringing together different experts from different loca- tions, extremely strong teams can be devel- oped. The virtual partnership model also brings considerable savings on equipment, other costly capital items and administrative costs, as these are typically provided by the research partners. Such in-kind contribu- tions are significant and can reduce costs in individual discovery and development pro- jects to sponsoring organizations by as much as 50% (costs of technologies, donated staff time, infrastructure, access to compound libraries and so on)30,31.

Organizations managing several projects also have the potential to develop long-term relationships with some partners to bring added stability to project management. For example, laboratories with expertise in drug

studies in the field of tropical/neglected dis- eases. Ongoing examples of drug discovery and development partnerships exploiting some of these approaches are listed in TABLE 2. Of the diseases of interest, at present only malaria and tuberculosis have a significant portfolio of projects spanning discovery and development. With increased activity in other disease areas it is hoped that these portfolios can now begin to be matched for other diseases.

Efficiency and cost-effectiveness of portfolio management of virtual R&D. An obvious advantage of the virtual model is its flexibil- ity. Projects can be terminated as necessary and replacement projects can be initiated at locations that already have the intellectual capacity and expertise to manage that project (for example, knowledge of a specific enzyme

Table 2 | Discovery and development public–private partnership projects* targeting neglected diseases

Disease Discovery Development Post-regulatory label extensions

Malaria Improved 4-aminoquinoline Rectal artesunate (TDR) Coartem in children of 5 kg weight (MMV, GSK, U. Liverpool) Chlorproguanil-dapsone-artesunate (TDR, Novartis) Farnesyltransferase inhibitors (MMV, TDR, GSK) Coartem paediatric form (MMV, TDR, Novartis) (MMV, BMS, U. Washington) Pyronaridine-artesunate Chlorproguanil-dapsone Manzamine derivatives (MMV, TDR, Shin Poong) (TDR, GSK) (MMV, U. Mississippi) Amodiaquine-artesunate Cysteine protease inhibitors (TDR, EU, DNDi) (MMV, U. California San Francisco, GSK) Mefloqine-artesunate Fatty acid biosynthesis inhibition (TDR, EU, DNDi) (MMV, Texas A&M, Albert Einstein/ Artemisone Howard Hughes, Jacobus) (MMV, Bayer, U. Hong Kong) Pyridone (MMV, GSK) Synthetic peroxide New dicationic molecules (MMV, Ranbaxy, U. Nebraska) (MMV, U. North Carolina, Immtech) i.v. artesunate Dihydrofolate reductase inhibition (MMV, WRAIR) (MMV, BIOTEC Thailand) Others under discusison

(MMV, TDR, WRAIR, MMV/U. Missisippi)

Tuberculosis Pyridones and quinolizines (GATB, PA824 Taejon South Korea, Yonsei Seoul Korea), (GATB, NIH, Johns Hopkins and others) Isoniazid analogue Moxifloxacin (GATB, Wellesley College MA, Veterans (GATB, CDC Atlanta, Bayer, Administration Medical Center NY) Johns Hopkins),

Others under discussion (TDR, GATB)

Leishmaniasis Paromomycin Miltefosine (IOWH, TDR) (TDR, Zentaris) Others under discussion (TDR, IOWH, DNDi)

African Novel diamidines Oral eflornithine trypanosomiasis (Gates, Immtech, U. North Carolina) (TDR, Aventis)

Novel diamidine (DB289) (Gates, Immtech, U. North Carolina) Project under negotiation (TDR, DNDi)

Chagas disease Azole (IOWH, Yale U.) Others under discussion (TDR)

Schistosomiasis Praziquantel combinations (TDR)

Onchocerciasis Project under negotiation (TDR)

Lymphatic filariasis Albendazole + ivermectin (TDR)

*Note that only projects actually initiated in partnership are presented. Projects under negotiation are not specifically named. BMS, Bristol-Myers Squibb; CDC, Centres for Disease Control; DNDi, Drugs for Neglected Diseases Initiative; EU, European Union; GATB, Global Alliance for Tuberculosis Drug Development; GSK, GlaxoSmithKline; IOWH, Institute for One World Health; MMV, Medicines for Malaria Venture; NIH, National Institutes of Health; TDR, Tropical Disease Research; WRAIR, Walter Reid US Army Institute of Research.

P E R S P E C T I V E S

addition to cooperation can develop, both for projects and for funding. This is healthy if managed intelligently, and the term ‘co- opetition’ has been coined to describe this situation. It might be that as multiple organi- zations develop, some realign their activities or even merge in a manner similar to the private sector. It must be emphasized that many PPPs are still in their infancy and are themselves social experiments. At the moment the prime challenge for all the organizations is to further scale up their activities, to better utilize the scientific, technical and partnership opportunities that exist, and to generate the new drugs that are needed.

To ensure the long-term sustainability of these programmes, greater involvement of disease-endemic countries has to be built into the PPP model. More focused and result- oriented technology transfer and capacity building will support a future role of dis- ease-endemic countries in discovering and developing the drugs they need.

Solomon Nwaka is at the Medicines for Malaria Venture, Geneva, Switzerland, and

Robert G. Ridley is at UNDP/World Bank/WHO Special Programme for Research and Training

in Tropical Diseases, Geneva, Switzerland. e-mails: [email protected]; [email protected]

doi:10.1038/nrd1230

1. Trouiller, P. et al. Drugs development for neglected diseases: a deficient market and a public health policy failure. Lancet 359, 2188–2194 (2002).

2. Mrazek, M. F. & Mossialos, E. Stimulating pharmaceutical research and development for neglected diseases. Health Policy (New York) 64, 75–88 (2003).

new drug concepts and pharmacophores is required for long-term impact and sustain- ability18,25,37. Within this context, the strength of individual project review is crucial. To quote from an industry R&D manager, “The difference between a pipeline and a sewer is what you put into it”.

Role of disease-endemic countries Most public organizations recognize that the impact and long-term sustainability of drug R&D for tropical diseases depends heavily on the development of research capacity in, and the engagement of, scientists and institu- tions in developing countries. Indeed, WHO/ TDR stress this as being integral to their mis- sion, as does the newly created DNDi. Many countries, such as India, China, South Korea and South Africa, now have the ability to pro- duce and manufacture drugs. Many countries also have expertise in some of the individual scientific components that are required to dis- cover and develop drugs. However, few have the capacity to perform the full spectrum of tasks required to move from early discovery research through to preclinical and clinical develop- ment, dossier preparation and registration6,58,59.

Several companies from advanced devel- oping countries are now partners in PPPs for tropical diseases. For some, although they have vast experience and expertise in process chemistry, production and manu- facture, it is the first time that they have developed, or co-developed, a new chemical entity. Many scientists from developing countries are also heavily engaged in indi- vidual PPP projects, particularly at the clinical development stage, and several sites now have the capacity to carry out Good Clinical Practice studies. Clinical developments, such as those that occurred recently for milte- fosine and chlorproguanil-dapsone, can be used as engines to further develop such capacity59. The recent creation of the European Developing Countries Clinical Trial Partnership60 is going to have a major impact in this area of activity, as will the cre- ation of the Strategic Initiative to Develop Capacity for Ethical Review61.

However, scientists in developing countries do not want to be just ‘testers and developers’ of other people’s products. They also want to participate in the discovery and develop- ment of new drugs. One area in which scien- tists in developing country have an inherent advantage is in leads and drug candidates derived from natural products and tradi- tional medicines. There is an increasing level of activity in this area. TDR is initiating activities with institutions and networks in developing countries to expand and organize

this activity. It is further complementing this with capacity building and training in bioinformatics9.

Future prospects Initial results from PPPs show that the virtual drug R&D model works, but it requires expe- rienced management and understanding of both the drug R&D process and the diseases, as well as of the different perspectives and needs of all the partners involved. The impor- tance of transparency and team work under the virtual model cannot be over emphasized. These factors are often as important as the science for the success of the project. The strengths and weaknesses of different types of organization presently involved in product R&D for neglected diseases are highlighted in TABLE 3. This assessment of the respective institutions is not exhaustive, but it is pro- vided to promote the debate on how best to discover, develop and deliver new products for neglected diseases and how organizations might continue to develop and adapt to meet these needs.

The status of drug R&D for neglected diseases today is encouraging, but more still needs to be done. Some argue that both the funding and focus of the existing initiatives are scattered and that there is some danger of duplication of effort and therefore redun- dancy2,12. Many of the organizations collab- orate and partner with each other, but undoubtedly an element of competition in

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Table 3 | Organizations involved in R&D for neglected diseases

Partnering Strengths Weaknesses organizations

Big pharma Strong drug R&D expertise; strong Bureaucracy: slow decisions; regulatory affairs; strong project a culture of controlling R&D management; strong marketing; collaboration internal resources for projects

Small pharma/ Specific drug R&D expertise; Drug R&D expertise not complete; biotech flexibility of decision making market knowledge often limited;

often lack internal resources for projects

Academia Strong basic research: biology/ Drug R&D expertise limited; desire genomics, target identification/ to publish early can conflict with validation; understand disease patenting; not used to project and can think ‘out of box’ management; limited commercial

understanding

CROs/ Strengths in specific areas of expertise: Few have broad expertise; where consultants management support, regulatory, expertise is broad, might bring

dossier preparation, toxicology bureaucracy; usually have to pay going market rates

Big public Knowledge of multiple diseases, Bureaucracy: slow decisions (WHO/TDR) health needs and systems in context;

links to governments; strong networks in disease-endemic countries; capacity-building focus

Small ‘public’ Focus on specific diseases; Young organizations: no products (MMV, GATB) flexibility of decision making delivered yet; limited developing-

country experience

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56. Rosenthal, P. J. et al. Cysteine proteases of malaria parasites: targets for chemotherapy. Curr. Pharm. Des. 8, 1659–1672 (2002).

57. MMV/GSK Press Release, June (2003) (see www.mmv.org).

58 Nwaka, S. Prospective antimalarial drug discovery and development. TDR Scientific Working Group on Malaria. March (2003).

59. Bhattacharya, S. Capacity building for clinical trials: the investigator’s perspective, TDR News 69, November (2002).

60. Medaglini, D. & Hoeveler, A. The European research efforts on HIV/AIDS, malaria and tuberculosis. Vaccines 21, S116–S120 (2003).

61. Dickson, D. WHO and industry combine to form ethics body. Nature Med. 8, 645 (2002).

62. Ridley, R. Antimalarial drug discovery and development: an industrial perspective. Exp. Parasitol. 87, 293–304 (1997).

63. Roberts, S. A. Drug metabolism and pharmacokinetics in drug discovery. Curr. Opin. Drug Discov. Devel. 6, 66–80 (2003).

64. Frantz, S. Screening the right candidate. Nature Rev. Drug Discov. 2, 331 (2003)

65. Di, L. & Kerns, E. H. Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. 7, 402–408 (2003).

66. Lipinski, C., Lombardo, F., Dominy, B. & Feeney, P. Experimental and computational approaches to estimate solubility in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).

67. Venkatesh, S. & Lipper, R. Role of the development scientist in compound lead selection and optimization. J. Pharm. Sci. 89, 145–154 (2000).

68. Keatley, K. L. A comparison of the U. S. EPA FIFRA GLP standards with the U. S. FDA GLP standards for nonclinical laboratory studies. Qual. Assur. 7, 147–154 (1999).

69. Molzon, J. The Common Technical Document: the changing face of the New Drug Application. Nature Rev. Drug Discov. 2, 71–74 (2003).

70. Tufts Center for the Study of Drug Development. Impact Reports (1999 and 2000).

71. Food and Drug Administration, HHS. International Conference on Harmonisation; guidance on M4 common technical document; availability. Notice. Fed Regist. 66, 52634–52637 (2001).

72. DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 157–185 (2003).

Acknowledgements We thank M. Bendig and D. Kioy for their assistance in conceptual- izing Box 3. We thank S. Campbell for his contributions to Box 4. We thank P. Rosenthal, C. Morel and C. Craft for critical reading of the manuscript.

Online links

FURTHER INFORMATION Drugs for Neglected Diseases Initiative: http://www.dndi.org/ Global Alliance for TB Drug Development: http://www.tballiance.org/ Institute for One World Health: http://www.oneworldhealth.org/ Medicines for Malaria Venture: http://www.mmv.org/pages/page_main.htm World Health Organization/Tropical Disease Reserch: http://www.who.int/tdr/ Access to this interactive links box is free online.

29. Nagle, T., Berg, C., Nassr, R. & Pang, K. The further evolution of biotech. Nature Rev. Drug Discov. 2, 75–79 (2003).

30. Kettler, H. & White, K. Valuing industry contributions to public–private partnerships for health product development. (Initiative for Public–Private Partnerships for Health, 2003).

31. Medicines for Malaria Venture. Annual Report (2002). 32. Coates, A. et al. The future challenges facing the

development of new antimicrobial drugs. Nature Rev. Drug Discov. 1, 895–909 (2002).

33. Ridley, R. G. Product R&D for neglected diseases: twenty- seven years of WHO/TDR experiences with public–private partnerships. EMBO Rep. 4, S43–S46 (2003).

34. Sundar, S. et al. Oral miltefosine for Indian visceral leishmaniasis. N. Engl. J. Med. 347, 1739–1746 (2002).

35. Lang, T. & Greenwood, B. The development of LAPDAP, an affordable new treatment for malaria. Lancet Infect. Dis. 3, 162–167 (2003).

36. Winstanley, P. Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria. Trop. Med. Int. Health 6, 952–954 (2001).

37. Medicines for Malaria Venture. Business Plan (2003). 38. Vennerstrom, J. L. et al. Spiro and Dispiro 1,2, 4-

trioxolanes antimalarials. US patent 6,486,199 filed (2002). 39. Report of the Advisory Committee on Health Research:

Genomic and world health. World Health Organization, Geneva (2002).

40. Gutierrez, J. A. Genomics: from novel genes to new therapeutics in parasitolgy. Int. J. Parasitol. 30, 247–252 (2000).

41. Rosamond, J. & Allsop, A. Harnessing the power of the genome in the search for new antibiotics. Science 287, 1973–1976 (2000).

42. Gardner, J. et al. Genome of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002).

43. Ersfeld, K. Genomes and genome projects of protozoan parasites. Curr. Issues Mol. Biol. 5, 61–74 (2003).

44. DiMasi, J. A. et al. Cost of innovation in the pharmaceutical industry. J. Health Econ. 10, 107–142 (1991).

45. Barry, C. E. et al. DNA microarrays and combinatorial chemical libraries: tools for the drug discovery pipeline. Int. J. Tuberc. Lung Dis. 4, S189–S193 (2000).

46. Buysse, J. The role of genomics in antibacterial target discovery. Curr. Med. Chem. 8, 1763–1776 (2001).

47. Murray D. M. & Shinket, R. Discovery and development of a genomic drug. Curr. Drug Disc. June, 27–33 (2003).

48. Mattieu, M. P. Parexel’s pharmaceutical R&D statistical sourcebook. Parexel International Corp. Waltham, MA (2002/2003).

49. Frost, L. & Reich, M. Mectizan donation program: origins, experiences, and relationships with coordinating bodies for onchocerciasis control. Boston, MA, Harvard School of Public Health (1998).

50. Hursey, B. S. The programme against African trypanosomiasis: aims, objectives and achievements. Trends Parasitol. 17, 2–3 (2001).

51. Guerin, P. J. et al. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect. Dis. 2, 494–501 (2002).

52. Zumla, A. Drugs for neglected diseases. Lancet Infect. Dis. 2, 393 (2002).

53. Antimalarial drug combination therapy. Report of WHO Technical Consultation (2001).

54. Stead, A. M. W. et al. Diamidine compounds: selective uptake and targeting in Plasmodium falciparum. Mol. Pharmacol. 59, 1298–1306 (2002).

55. Gelb, M. H. et al. Protein farnesyltransferases: piggy- back medicinal chemistry targets for the development of antitrypanosomatids and antimalarial therapeutics. Mol. Biochem. Parasitol. 126, 155–163 (2003).

3. Haffner, M. E., Whitley, J. & Moses, M. Two decades of orphan product development. Nature Rev. Drug Discov. 1, 821–825 (2002).

4. Trouiller, P. et al. Drugs for neglected diseases: a failure of the market and public health failure. Trop. Med. Int. Health 6, 945–951 (2001).

5. Sachs, J. The link of public health and economic development. Office of Health Economics, London (2001).

6. Kettler, H. E. & Modi, R. Building local research and development capacity for prevention and cure of neglected diseases: the case for India. Bull. World Health Organization 79, 742–747 (2001).

7. Medecins Sans Frontieres Access to Essential Medicines Campaign. Fatal imbalance, the crises in research and development for drugs for neglected diseases (2001).

8. Reich, M. R. The global drug gap. Science 287, 1979–1981 (2000).

9. Remme, J. F. H. et al. Strategic emphasis for tropical disease research. A TDR perspective. Trends Parasitol. 18, 421–426 (2002).

10. Nossal, G. J. Modern medicine and global communi- cable diseases: new partnerships for progress. Aust. NZ J. Med. 30, 267–271 (2000).

11. Yamey, G. Public sector must develop drugs for neglected diseases. BMJ 324, 698 (2002).

12. Kettler, H. & Towse, A. Public–private partnerships for research and development: medicines and vaccines for diseases of poverty. Office of Health Economics, London (2002).

13. Bruneton, C. et al. The drug trade between European countries and developing countries. Med. Trop. (Mars) 57, 375–379 (1997).

14. Global Forum for Health Research. The 10/90 report of research 2001–2002. Global Forum for Health Research, Geneva (2002).

15. Widdus, R. Public–private partnerships for health: their main targets, their diversity, and their future directions. Bull. World Health Organization 79, 728–734 (2001).

16. Macroeconomics and Health: Investing in Health for Economic Development. Report of the Commission on Macroeconomics for Health, World Health Organisation, Geneva (2001).

17. Veekan, H. & Pecoule, B. Drugs for ‘neglected diseases’: a bitter pill. Trop. Med. Int. Health 5, 309–311 (2000).

18. Froese, E. H. Meeting the pharmaceutical needs of a developing country. World Health Forum 12, 25–28 (1991).

19. Bryceson, A. Current issues in the treatment of visceral leishmaniasis. Med. Microbiol. Immunol. (Berl.) 190, 81–84 (2001).

20. Legros, D. et al. Treatment of human African trypanosomiasis: present situation and needs for research and development. Lancet 2, 437–440 (2002).

21. Seawort, B. J. Multidrug-resistant tuberculosis. Infect. Dis. Clin. North Am. 16, 73–105 (2002).

22. Rosenthal, P. J. Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery (Humana, Totowa, 2001).

23. Morel, C. M. Reaching maturity: 25 years of the TDR. Parasitol. Today 16, 503–551 (2000).

24. Ridley R. G. Putting the partnership into public–private partnerships. Bull. World Health Organization 79, 694 (2001).

25. Ridley, R. G. Medical need, scientific opportunity and the drive for antimalarials. Nature 415, 686–693 (2002).

26. TDR News. MMV: New Medicines for Malaria Venture. February (1999).

27. Wheeler, C. & Berkley, S. Initial lessons from public–private partnerships in drug and vaccine development. Bull. World Health Organization 79, 728–734 (2001).

28. Ridley, R. G. et al. Round table. A role of public–private partnerships in controlling neglected diseases. Bull. World Health Organization 79, 771–777 (2001).