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 cannot cater for diseases for which commercial incentives are insufficient to trigger private sector investments in R&D1, 2. In the developed 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 diseases6-8. They include diseases such as malaria, tuberculosis, African trypanosomiasis (sleeping sickness), Chagas disease, dengue, leishmaniasis, schistosomiasis, onchocerciasis and lymphatic filariasis9-11. Additional factors that further depress the market for innovative new drugs for these diseases include poor regulatory infrastructure in many countries and competing counterfeit 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 consolidated public–private and philanthropic approach that stimulates R&D for these diseases 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 governance 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 intellectual 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 conversion 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 the development of new and affordable drugs12, 17, 18. The few existing drugs often fail due to the emergence of resistance, have significant compliance and safety issues, or are inaccessible due to lack of affordability and/or appropriate infrastructure19-22. 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 molecular and structural biology, medicinal chemistry and robotics in the 1980s and 1990s. With the availability of several parasite 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 discovery and development between public-sector organizations and private companies to be established. This process has rapidly accelerated since the late 1990s, for example, through the creation of the Medicines for Malaria Venture (MMV)24-26 and other organizations, 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 development (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 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 flexibility within the industry, as pharma companies have increasingly sought deals with others to co-develop products and/or commercialize them. The fact that fully integrated pharmaceutical companies seek and contract with partners with specific R&D expertise, even for such activities as lead optimization, coupled with the concept of developing R&D partnerships based on venture 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 complemented by some important industry initiatives. 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 established Diseases of the Developing World Initiative that includes dedicated drug discovery 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 companies 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 companies 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 affordable12, 15, 30. This calls for a product-focused approach, for which the required mindset, until recently, was only found in the pharmaceutical 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 management differences and style required at the discovery and development stages, the overlap of tasks between industry and academia in a partnership-managed process, and based on MMV calculations for competitively selected malaria projects, the probability of moving from one stage to the other through the process31. As for all R&D projects, 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. Furthermore, there is a need to continually evaluate individual projects against the overall needs and situation of the global R&D portfolio. A more flexible management approach is required at the exploratory and discovery stages of the process than at the development 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 compound 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 registration 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 consultants, 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 recommendation of project termination. This enables a full range of expertise to feed into decisions and reassures collaborators that the decisions are fair and unbiased. Most organizations 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 partnerships involve millions of dollars and commit organizations to work together over several years, legal agreements are required, just as in a business environment. The agreement 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 industrial partners. The public sector, through rights obtained in the agreement, requires a commitment from the commercial partner, with respect to both manufacturing and providing 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 companies 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 intellectual property to be utilized within the services of the project, but they wish to limit any prospect of it somehow becoming available to 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 development 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 management and commit to delivering specific pieces of work within given timelines that facilitate an integrated development plan.
This concept has now been put into operation 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 programme, 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 leishmaniasis34 and for the development of chlorproguanil-dapsone with GlaxoSmithKline 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 pharmaceutical company partner might lack the necessary infrastructure to cover regulatory 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 contract research organizations to help manage the process of development, to facilitate 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 widespread attention and debate.
Virtual drug discovery. Extending the product development team concept to drug discovery is logical, but creates a unique set of challenges. 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 commissioning discrete packages of work that ultimately combine to form the dossier. Virtual drug discovery, however, especially in the early stages, requires a far more continuous, 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 discovery 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 development31, 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 commitment 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 quarterly 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 candidate selection, there was greater coordination of activities and more assertive central project management. The early establishment 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 promise for neglected diseases. It could have broader relevance for the pharmaceutical industry as a whole as it seeks new paradigms to enhance its productivity. Some pharma companies are increasingly contracting out areas of discovery that had previously been performed internally; for example, the structural determination of protein–ligand complexes, medicinal chemistry 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 interface with post-regulatory studies (downstream interface). The second is the interface 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 traditional public-sector organizations that invest in these diseases, whether they be science research agencies (upstream) or disease control agencies (downstream).
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 development 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 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 revolutionize drug discovery39-41. The next big challenge in tropical diseases is determining 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; however, 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 modelling and screening, and X-ray crystallography are facilitating both our understanding of infectious organisms and our competence at rational drug design, as well as increasingly 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 development 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 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 development, 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 considered, 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 management. 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 leishmaniasis, respectively34, 50-52. Paromomycin, originally developed for oral use against gut pathogens, is now in Phase III trials sponsored 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 combinations 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, improvements 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 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 relevance for a tropical disease indication. For example, farnesyl transferases have been identified as potential targets for malaria and African trypanosomiasis, and projects have started taking advantage of medicinal chemistry on human farnesyl transferase inhibitors for cancer55. Similarly, cysteine proteinases have been identified as targets for malaria and Chagas disease, and projects have been initiated 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 studies in the field of tropical/neglected diseases. 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 flexibility. 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 in a given university; access to a specific class of compounds at a company). By bringing together different experts from different locations, extremely strong teams can be developed. 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 contributions are significant and can reduce costs in individual discovery and development projects 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 testing against parasites might be utilized as a resource for several projects. Clinical investigators might be utilized for numerous projects. Similarly, a small group of preferred contract suppliers might be used for outsourced preclinical work or regulatory support. An interesting concept was recently initiated by MMV and the GlaxoSmithKline Diseases of the Developing World programme. 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 continuous investment in innovation to identify new drug concepts and pharmacophores is required for long-term impact and sustainability18, 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 institutions in developing countries. Indeed, WHO/ TDR stress this as being integral to their mission, as does the newly created DNDi. Many countries, such as India, China, South Korea and South Africa, now have the ability to produce and manufacture drugs. Many countries also have expertise in some of the individual scientific components that are required to discover 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 development, dossier preparation and registration6, 58, 59.
Several companies from advanced developing countries are now partners in PPPs for tropical diseases. For some, although they have vast experience and expertise in process chemistry, production and manufacture, 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 individual 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 miltefosine 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 creation 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 development of new drugs. One area in which scientists in developing country have an inherent advantage is in leads and drug candidates derived from natural products and traditional 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.
Initial results from PPPs show that the virtual drug R&D model works, but it requires experienced 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 importance 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 provided 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 redundancy2, 12. Many of the organizations collaborate and partner with each other, but undoubtedly an element of competition in 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 organizations 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 disease-endemic countries in discovering and developing the drugs they need.