Brief History Of Biomarker Research 19982008 The First Decade

During the last decade of the twentieth century, biomedical research underwent one of the most dramatic periods of change in history. Influenced by a multitude of factors—some scientific, others economic, and still others of policy—new frontiers of science emerged as technology and knowledge converged, and diverged—bringing new discoveries and hope to the forefront of medicine and health. These capabilities came about as a generation 's worth of science that brought to the mainstream of biomedical research the foundation for a molecular basis of disease: recombinant DNA technology. Innovative applications of lasers, novel medical imaging platforms, and other advanced technologies began to yield a remarkable body of knowledge that provided unheralded opportunities for discovery of new approaches to the management of human health and disease.

Here we briefly revisit a part of the medical research history that led to the shaping of new directions that is, for now, captured simply by the term

BRIEF HISTORY OF BIOMARKER RESEARCH, 1998-2008: THE FIRST DECADE 17

biomarker, a biological indicator of health or disease. In looking backward to the 1980s and 1990s and the larger scheme of health care, many new challenges were being faced. The international challenges and global economic threats posed by human immunodeficiency virus (HIV) and AIDS provided the impetus for one of the first steps in target-designed therapies and the use of viral and immune indicators of disease. For the first time, strategically directed efforts in discovery and clinical research paradigms were coordinated at the international level using clinical measures of disease at the molecular level. The first impact of biomarkers on discovery and translational research, both privately and publicly funded, as related to biological measures of viral load, CD4+ T-lymphocyte counts, and other parameters of immune function and viral resistance came to be a mainstay in research and development. Regulatory authority was put in place to allow "accelerated approval" of medical products using surrogate endpoints for health conditions with grave mortality and morbidity. Simultaneously, clinical cancer therapeutics programs had some initial advances with the use of clinical laboratory tests that aided in the distinction between responders and nonresponders to targeted therapies. The relation of Her2/neu tyrosine kinase receptor in aggressive breast cancer and response to (Herceptin) [1] i and similarly, the association of imatinib (Gleevac) responsiveness with the association of the presence of Philadelphia chromosome translocation involving BCR/Abl genes in chronic myelogenous leukemia [2], represented some of the cases where targeted molecular therapies were based on a biomarker test as a surrogate endpoint for patient clinical response. These represented the entry point of pharmaceutical science moving toward co-development, using diagnostic tests to guide selection of therapy around a biomarker.

Diverse changes were occurring throughout the health care innovation pipeline in the 1990s. The rise of the biotechnology industry became an economic success story underpinned by successful products in recombinant DNA technology, monoclonal antibody production, and vaccines. The device manufacturing and commercial laboratory industries became major forces. In the United States, the health care delivery system underwent changes with the widespread adoption of managed care programs, and an effort at health care reform failed. For U.S.-based academic research institutions, it was a time of particular tumult for clinical research programs, often supported through clinical care finances, downsized in response to financial shortfalls. At a time when scientific opportunity in biomedicine was, arguably, reaching its zenith, there were cracks in the enterprise that was responsible for advancing basic biomedical discovery research to the clinic and marketplace.

In late 1997, the director of the National Institutes of Health, Harold Varmus, met with biomedical research leaders from academic, industrial, governmental, and clinical research organizations, technology developers, and public advocacy groups to discuss mutual challenges, opportunities, and responsibilities in clinical research. In this setting, some of the first strategic considerations regarding "clinical markers" began to emerge among stake holders in clinical research. From a science policy perspective, steps were taken to explore and organize information that brought to light the need for new paradigms in clinical development. Some of these efforts led to the framing of definitions of terms to be used in clinical development, such as biomarkers (a characteristic that is measured and evaluated objectively as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention) and surrogate endpoints (a biomarker that is intended to substitute for a clinical endpoint and is expected to predict clinical benefit or harm, or lack of benefit or harm, based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence) and descriptions of the information needs and strategic and tactical approaches needed to apply them in clinical development [3] . A workshop was held to address statistical analysis, methodology, and research design issues in bridging empirical and mechanism- based knowledge in evaluating potential surrogate endpoints [ 4] . In - depth analyses were held to examine information needs, clinical training skills, database issues, regulatory policies, technology applications, and candidate disease conditions and clinical trials that were suitable for exploring biomarker research programs. As a confluence of these organizational activities, in April 1999 an international conference was hosted by the National Institutes of Health (NIH) and U.S. Food and Drug Administration (FDA) [5]. The leadership focused on innovations in technology applications, such as multiplexed gene analysis using polymerase chain reaction technologies, large-scale gel analysis of proteins, and positron-emission tomography (PET) and magnetic resonance imaging (MRI). A summary analysis was crafted for all candidate markers for a wide variety of disease states, and a framework was formed for multiple disease-based public-private partnerships in biomarker development. A series of research initiatives supported by industry, NIH, and FDA were planned and executed in ensuring months. New infrastructure for discovery and validation of cancer biomarkers was put in place. Public-private partnerships for biomarker discovery and characterization were initiated in osteoarthritis, Alzheimer disease, and multiple sclerosis. Research activities in toxicology markers for cardiovascular disease and metabolism by renal and hepatic transformation systems were initiated by FDA. These events did not yield a cross-sector strategic action plan, but did serve as a framework for further engagement across governmental, academic, industrial, and nongovernmental organizations. Among the breakthroughs was the recognition that new statistical analysis methods and clinical research designs would be needed to address multiple variables measured simultaneously and to conduct metaanalyses from various clinical studies to comprehend the effects of a biomarker over time and its role as a reliable surrogate endpoint. Further, it was recognized that there would be needs for data management, informatics, clinical registries, and repositories of biological specimens, imaging files, and common reagents.

Over the next several years, swift movement across the research and development enterprise was under way. It is obvious that future biomarker research

TABLE 1 Major Scientific Contributions and Research Infrastructure Supporting Biomarker Discovery

Human Genome Project

Mouse models of disease (recombinant DNA technology)

Information management (informatics tools, open-source databases, open-source publishing, biomarker reference services) Population-based studies and gene-environment interaction studies Computational biology and biophysics Medical imaging: structural and functional

High-throughput technologies: in vitro cell-based screening, nanotechnology platforms, molecular separation techniques, robotics, automated microassays, high -resolution optics Proteomics, metabolomics, epigenomics Pharmacogenomics Molecular toxicology Genome-wide association studies

Molecular pathways, systems biology, and systems engineering was driven in the 1990s and early years of the twenty-first century by the rapid pace of genome mapping and the fall in cost of large-scale genomic sequencing technology, driven by the Human Genome Project. A decade later, it is now apparent that biomarker research in the realm of clinical application has acquired a momentum of its own and is self-sustaining.

The major schemes for applications of biomarkers can be described in a generalized fashion in four areas: (1) molecular target discovery, (2) early-phase drug development, (3) clinical trials and late-stage therapeutic development, and (4) clinical applications for health status and disease monitoring. The building blocks for biomarker discovery and early-stage validation over the last decade are reflected in Table 1. Notable to completion of the international Human Genome Project was the vast investment in technology, database development, training, and infrastructure that have been applied throughout industry toward clinical research applications.

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