Introduction
In recent decades, scientific advances in many disciplines, particularly molecular biology, genomics, and medicinal chemistry, opened the way for developing new therapeutic agents, several vaccines, and enhanced diagnostic capabilities. The central questions for the purpose of this chapter are what drives research, discovery, and development and what institutional and financing arrangements are necessary to promote research and development (R&D) for global diseases? Medical needs and public health imperatives constitute the logical answer to the first question; however, our armamentarium for combating major global diseases suffers from certain fundamental gaps. Innovation or discovery in the health fields is the process whereby the findings of many sciences are translated from basic findings into approaches to protect health (vaccines) or reverse disease (therapeutic and diagnostic products). Even though investigators have explored the conceptual framework for understanding how knowledge may be translated into products over the years, consensus is lacking on the specific drivers of the process or on the effects of alternative institutional arrangements.
Several features of the innovation process and its environment are essential for product development (Hilleman 2000; Nederbragt 2000; Schmid and Smith 2002). Innovation advances through a sequence of steps from discovery, through process development, to animal and human testing—a sequence with many overlapping features. Discovery may come in two ways: in a nonlinear, quantum-leap fashion that results in findings of an unexpected or unpredictable nature or in a linear fashion that builds on existing knowledge. Nonlinear processes are characteristically random despite many efforts to inject varying degrees of predictability or goal definitions (Webber and Kremer 2001). By contrast, the goal of linear innovation is defined improvement of a known process or mechanism.
Discovery
Product development is fundamentally anchored to the discovery process. In modern societies, discovery represents a societal capability that involves multiple institutions and constituents. The concept of networks of innovation has been introduced to describe one of the processes of discovery that leads to the development of pharmaceutical products or vaccines (Galambos and Sewell 1995, 272). Original scientific observations are made in organizations widely distributed across society, such as academic environments, government laboratories, biotechnology companies, or the large organizations dedicated to R&D. Because of the multiplicity of these settings and the traditions of open scientific communications, combined with the high costs of research and the importance of incentives, intellectual property issues must be taken into account.
The outcome is appreciably complex. Therefore, prescribing in a systematic way how to develop products along a planned pathway—particularly those intended for use in developing countries—is challenging. Recent decades have witnessed many attempts to develop specific drugs or vaccines to meet developing countries'needs, and the process has been difficult. Examples include pharmaceuticals to treat major global killers such as malaria and African trypanosomiasis and vaccines for most of the diarrheal diseases and respiratory infections (Nossal 2000).
Development Cycles
Discovery may set in motion a series of steps that eventually leads to the deployment of a product suitable for human use. The next step following discovery is process definition to map the steps of manufacturing and scalability to optimize the size of manufacturing. This process involves translating an idea discovered anywhere in the multiplicity of settings defined earlier, including mobilizing the energies of many sciences, to come up with a product. For instance, for a discovery in the therapeutic field to be translated into a drug, the sciences of medicinal chemistry, structural biology, and structure-function relationships are fundamental to the process. More recently, the product development process has begun using genomics and proteomics to bring about a more focused approach to defining clinical candidate products. Only then are pharmacology, toxicology, and bioavailability used in the next phase of therapeutic evaluation.
The capabilities for process definition and scalability have traditionally been concentrated in the research-based pharmaceutical industry, but several recent successful efforts in public-private partnerships (PPPs) have expanded these capabilities, such as the Medicines for Malaria Venture (MMV) and Global Alliance for TB Drug Development (GATB). Developing countries such as Brazil, India, and the Republic of Korea are now undertaking major efforts to achieve similar capabilities (Biehl 2002; Lohray 2003).
Therapeutic evaluation may begin at an in vitro or molecular level before proceeding to animal testing and the usual three phases of human assessment (Hilts 2003). The scientific disciplines of clinical research, epidemiology, and biostatistics have progressed at a significant pace in recent decades. In parallel, ethical and societal concerns about research involving human subjects and its standards, particularly across countries, cultures, and capabilities, are being extensively debated (Agre and Rapkin 2003; Barrett and Parker 2003; Emanuel and others 2004; McMillan and Conlon 2004).
The engineering aspects of product development are the next major step. Optimizing manufacturability and assessing market needs to determine the level of investment required for plant construction and operation are the two fundamental components of this phase.
One important feature of discovery and development is the length of time it takes. Estimates indicate that the average time for a new chemical entity (NCE) or vaccine to proceed from discovery through preclinical testing, human clinical trials, and regulatory approval is longer than a decade (Garber, Silvestri, and Feinberg 2004; Hilleman 1996; Rappuoli, Miller, and Falkow 2002), including the time spent on unsuccessful attempts. This timeline imposes certain pressures on how decisions are made, on the investment needed, and on competing priorities.
Development Institutions
As indicated previously, innovation and discovery occur in a multiplicity of settings. Although these settings have been concentrated in developed counties and have served the process of product development well, the challenges of developing new products for the developing world are considerable. Many countries, such as Brazil, India, and Singapore, are initiating a new wave of fundamental research institutions (Ahmad 2001; Jayaramann 2003). Their involvement in the discovery of products necessary for the health needs of developing countries is a fundamental paradigm shift. Along with the developing world's emerging biotechnology industry, a movement toward product discovery and development is under way. In addition, multiple PPPs—for example, the MMV (2002) and the GATB (2001)—are adding to the total global effort (Lyles 2003; Widdus 2001). The major feature of these new settings is their ability to focus on the immediate needs of developing countries. The challenge, however, lies in sustaining their funding and ensuring their ability to proceed from discovery to development and manufacturing, possibly with appropriate partners.
Finally, the evaluation of a product's pharmacological, biological, and toxicological properties may be carried out in developed or developing countries. Indeed, the evaluation of the safety and efficacy of products intended for developing countries should occur in those settings. Although quality control standards should be applied globally (Milstien and Belgharbi 2004), specific efforts must be directed at protecting the rights of human subjects (Agre and Rapkin 2003; Barrett and Parker 2003; Emanuel and others 2004; McMillan and Conlon 2004). In general, clinical development is heavily regulated in developed countries, and additional mechanisms exist for monitoring other aspects of product development, such as animal experimentation, use of controlled substances, and so on, but the global situation varies considerably. The time is ripe to consider the development of a global coordinated effort that involves uniform standards and reciprocity.
The analysis in the following sections focuses on the costs of developing drugs, vaccines, and diagnostics. The emphasis on drugs and vaccines reflects both the available evidence and the fact that regulatory requirements and costs are much greater for drugs and vaccines than for devices and diagnostics.
