Individualized Medicine and the Imperative of Global Health (2007)

Advances in molecular medicine have expanded the therapeutic armamentarium, offering effective interventions across the spectrum of diseases.1 The ongoing revolution in biomedical technology has transformed the comprehension of human health, microbial biology, and disease pathogenesis, redefining clinical pharmacology in the context of discovery and translation, as well as the role of the clinical pharmacologist as the bridge between the laboratory and the patient—and hence to the population at large. The integration of discovery in molecular diagnostics driving development of therapeutic solutions has underscored the importance of identifying and applying tools for disease prognosis, prediction, cure, and, ultimately, prevention in pursuit of individualized medicine. Indeed, the application of individualized medicine has emerged as instrumental in realizing the clinical value of the new biology, driving translation of discovery to evidence-based practice. The promise of individualized medicine and its impact on therapeutics, leveraging the emerging areas of combinatorial pharmacogenetics, targeted interference with disease, molecular immunology and vaccinology, and stem cell–based tissue engineering and regeneration importantly extends beyond single patients to populations of all ages in pursuit of targeted eradication of disease.2 In that context, the full impact of individualized medicine will be largely achieved only in its most global application to world health.1 In sharp juxtaposition to the transformative perspective offered by individualized medicine, the vision of global health provides Herculean challenges. Despite the continuous innovations in antimicrobial medicine, infectious diseases continue to devastate global populations (Figure 1), with more than 90% of deaths produced by only a handful of agents and associated diseases.3 In fact, lower respiratory infections are the leading single cause of mortality (Figure 2) and a primary cause of death for children under 5 years of age, killing approximately 4 million people annually. Most deaths occur in developing countries where children's immune systems are often compromised by malnutrition and co-morbidities. Bacterial pneumonia is the most serious of the lower respiratory infections, despite the existence of a spectrum of potent antimicrobials, which are commonly unavailable to affected populations. Infection with HIV has grown to pandemic proportions and is the second leading cause of death from infectious diseases, resulting in about 65 million infections and 25 million deaths worldwide.4 In 2005, approximately 2.8 million persons died from AIDS, 4.1 million were newly infected with HIV, and 38.6 million were living with HIV. Inadequate sanitation and access to clean drinking water are major contributors to the epidemic of diarrheal diseases, the third leading single cause of morbidity and mortality, and a leading cause of pediatric morbidity and mortality for children under 5 years of age, killing approximately 2 million people annually (Figure 2).3 Tuberculosis is the fourth leading cause of death associated with infectious diseases globally, with 9 million new cases and about 2 million deaths annually, latently infecting about 2 billion people, or one-third of the world's population.3,5,6 More than half of the world's population is at risk of acquiring malaria, and more than 500 million cases occur worldwide each year, resulting in over 1 million deaths annually, more than 80% affecting young children.3,7,8 Despite the development of effective vaccines, measles is still a major childhood killer in developing countries, causing about 0.6 million deaths annually.3 Children account for more than 50% of measles deaths annually, and the disease is responsible for 4% of total deaths in children each year. Cardiovascular, infectious, and neoplastic diseases are the principal contributors to the global disease burden. Leading individual causes of global morbidity and mortality. Beyond microorganisms, chronic and neoplastic diseases have ascended to leading roles on the global health stage. Collectively, cardiovascular diseases have become by far the most prevalent cause of morbidity and mortality around the world, affecting countries irrespective of income or socioeconomic status (Figure 1), exacerbated by the epidemic of obesity and diabetes.9 At the beginning of the 20th century, cardiovascular diseases accounted for less than 10% of all deaths worldwide. In striking contrast, at the beginning of the 21st century they account for about 50% of all deaths in the developed world and 25% in the developing world, and by 2020 will claim 25 million lives each year. Moreover, cancer is now the third leading cause of morbidity and mortality worldwide (Figure 1), and rates may further increase by 50% to 15 million new cases in the year 2020 (ref. 10). In 2000, malignant tumors were responsible for 12% of the nearly 56 million deaths worldwide from all causes. In many countries, more than a quarter of deaths are attributable to cancer. In 2000, 5.3 million men and 4.7 million women developed a malignant tumor, and, overall, 6.2 million died from the disease. Cancer has emerged as a major public health problem in developing countries, matching its effect in industrialized nations. Major contributors to the escalation in cancer incidence and mortality include lifestyle issues such as tobacco use, poor diet, and obesity. Although there is universal concurrence on health as a fundamental human right,11 this philosophical agreement belies a deeper incongruent and disturbing reality. The vision is that all humans have access and availability to quality services, including pharmacotherapeutics, that provide for an acceptable level of health care. However, translation of this vision has been undermined and the global war on human disease and disability compromised by the well-established and well-recognized intersection of political, social, economic, and scientific issues, including deteriorating health, social and political systems, the imbalance in the distribution of global wealth and resources, growing drug and insecticide resistance, climate change and natural disasters, and devastating conflicts. Beyond these large transnational issues, there is another substratum of complexities that opposes the realization of the envisioned future in universal health, affecting the health-care continuum from discovery through delivery to affected populations. The financial imperative of the global pharmaceutical marketplace and the associated intellectual property issues protecting proprietary drugs constricts development of pharmacotherapeutics targeted to diseases affecting the poorest countries.11 Médecins Sans Frontires estimates that 90% of the global health research and development expenditure is devoted to conditions that affect just 10% of the world's population, with priority conditional on ability to pay.11 This prioritization of diseases affecting the developed world is reflected in the fact that, of 1,393 new drugs approved between 1975 and 1999, only 13 were specifically indicated for tropical diseases, which largely affect the poorest populations and account for 12% of the global disease burden.11 Beyond discovery and development, the capacity to manufacture high-quality pharmaceuticals is globally restricted, largely limiting the availability of safe and effective medicines to industrialized countries.12 Furthermore, the health-care infrastructure required for application of modern pharmacotherapeutics is absent in many countries, limiting the number of possible clinical interventions. For example, although neoplastic diseases remain the third leading cause of morbidity and mortality worldwide, access to even the most inexpensive cytotoxic drugs is limited to those countries in which hospitals can offer the specialized support required to manage such patients.12 Finally, in many of the poorest countries, the distribution of critically needed therapeutic interventions is frequently inadequate, reflecting ineffective social structures, cultural taboos, and/or an obstructive political environment.12 Together, these issues conspire to undermine even the most meager attempts to provide minimum access to health care to those who most require it. In this morass of social, political, and economic uncertainty, can science, clinical pharmacology, and individualized medicine contribute to a path forward to improving global health? In the context of the focus across the continuum of drug discovery, development, regulation, and utilization, clinical pharmacologists are uniquely well positioned to serve as change agents in this global struggle. The role of individualized medicine and the discovery–translation paradigm offer emerging solutions to crises in health-care delivery, providing continually evolving therapeutic strategies, including molecular vaccinology, the identification of druggable targets of pathogenesis through genomics and proteomics, and the impact of pharmacogenomics to better individualize patient therapies by prognostic and predictive subsetting of patient populations and avoiding life-threatening adverse events.13 Furthermore, the shift from palliation to curation with the revolution in regenerative medicine and therapeutics offered by individualized medicine has the potential to transform the efficiency of disease resolution, shortening hospital stays and decreasing health-care expenditures.13 Beyond discovery and translation, new paradigms are being established that complement traditional models of drug development. For example, a collaboration between the Gates Foundation and the Institute for OneWorld Health is spearheading a new ideal of global drug development that is not for profit, removing the economic imperative constraining pharmaceutical companies and permitting a focus of resources and intellectual assets on developing drugs that benefit the most needy. Moreover, the World Health Organization is advancing the paradigm of the Essential Medicines List for adults and children, representing a focused group of medicines selected to meet priority needs, which contributes to better health care, drug management, and use of financial resources, creating greater access to care that is most relevant in the setting of developing countries.12,14,15 Certainly, the considerable challenges of global health require novel solutions that go beyond science and medicine, including new economic and social structures and political beneficence for the most vulnerable world citizens. However, clinical pharmacology and individualized medicine can contribute to creative solutions to these global problems. Individualized medicine draws from across all life sciences, providing a common enabling platform for discovery, development, and clinical application that offers better therapeutic interventions for the diseases plaguing the citizens of the poorest countries.16 The strength and uniqueness of the discipline are rooted in its comprehensive systems approach, in which the integrated development of diagnostics and therapeutics reflects the productivity of the discovery and development components. The overarching goal of the discipline, defined by this systems integration, is to enhance the medical management of global populations by ensuring the availability of innovative, effective, and safe diagnostic and therapeutic modalities. S.A.W. is the Samuel M.V. Hamilton Endowed Professor of Thomas Jefferson University. A.T. is the Marriott Family Professor of Cardiovascular Research of the Mayo Clinic. The authors declared no conflict of interest.