Title of proposed idea Centers for Research and Training in Quantitative and Systems Pharmacology
Nominator: NIH Institutes/Centers
Major obstacle/challenge to overcome: The focus of most of modern drug discovery has been on creating Ehrlich’s “magic bullet,” a drug that would hit only one target in the body effecting the desired change. This model has been enormously helpful and led to many drug successes. Yet even today, ninety percent of investigational drugs—i.e., those approved for trial—fail before being approved for use in patients. Many of these failures occur at the Phase II clinical trial level of development, making the failures very costly, and the majority fail for reasons of lack of efficacy. Furthermore, all drugs have unintended effects as well as intended ones, and drugs show person to person variability in their effectiveness and toxicities. Clearly, we can identify potential targets and make high affinity ligands for those, but we lack 1) a comprehensive knowledge of the role of these targets in human physiology and disease, 2) a quantitative and multi-scale understanding of how the targets modulate each other, and 3) how hitting more than one target sums to produce an observable phenotypic change. Industry scientists confirm that these are major impediments for drug discovery and development in most therapeutic areas.
We submit that there is a profound need to make a major shift in our approach to drug discovery and understanding drug action to fill in the context within which targets operate and how they produce their therapeutic action and side effects. This proposal is not meant to encompass all of systems biology or pharmacology, but to add a more quantitative and integrative perspective to allow a systems level understanding of drug action. Academic pharmacology, for the past thirty to forty years, has been largely focused on molecular pharmacology, providing an in depth understanding of individual molecular targets within the body. There has also been a diminished level of academic research in clinical pharmacology, the discipline most aligned with understanding drug action. There is now a timely and urgent need to stimulate Quantitative and Systems Pharmacology (QSP), an emerging discipline that proposes to build from an understanding of a drug's molecular interactions to an understanding of its temporal and dynamic modulation of cellular networks, impact on human pathophysiology, and optimal use in the clinic. QSP builds upon classical and molecular pharmacology by adding omics approaches not available in earlier periods and recent modeling approaches that enable the deciphering of high volume data analysis. It adds the horizontal integration and numerical quantitation of biological processes and mechanisms provided by systems biology and the vertical integration and statistical approaches characterized by PD/PK modeling and clinical pharmacology. It is necessarily multi-disciplinary and highly integrative, operating across the biological hierarchy from biochemistry and cells to tissues and whole organs to animal studies and human patients. Furthermore, for research to move rapidly in this emerging area, there must be a scientific workforce to drive it; currently, this is also an underserved need.
Emerging scientific opportunity ripe for Common Fund investment: This recommendation arises from two workshops and a follow up white paper held at the NIH in 2008 and 2010 (http://meetings.nigms.nih.gov/?ID=8316) with participants from academia, industry and government. The stimulus for the workshops was the lack of integration taking place between the pharmacology and the systems biology being supported by NIH and the need to address the poor success rate in drug discovery and development. The workshops brought together researchers in pharmacology, systems biology, pharmacokinetics/pharmacodynamics, computer modeling and related areas with a focus on how systems biology was contributing to drug discovery and understanding of drug action now and in the future. The major result of the first meeting was a strong recommendation to repeat the workshop. The attendees recognized that they had something to offer each other, but felt they were currently far apart. The second workshop focused on three different therapeutic areas with the idea that they could learn from each other’s successes and failures. That QSP encompasses cells, organs, and virtually all therapeutic areas, with underlying principles to be discovered that span all these makes it highly appropriate for a Common Fund proposal. The opportunity now exists to bring together researchers in these various areas in a common effort to expand our knowledge of drug action beyond drug target interactions to an understanding of how to use drugs alone or in combination to control biological systems that can produce shifts between disease and healthy phenotypes.
Common Fund investment that could accelerate scientific progress in this field: The purpose of this Common Fund idea is to promote the use of QSP approaches for the study and elimination of a major roadblock in drug discovery and development, the complexity of drug targeting. The centers mechanism is recommended to facilitate collaborative development of pioneering research, research training, and outreach programs in this emerging area and therefore stimulate the field as a whole. The focus of the centers should be the generation and testing of new ideas in QSP. The primary justification for centers is the need for integration of research plus training, and integration across levels of biological organization, across scientific disciplines, and across therapeutic areas. We believe that a community is emerging from the cognate disciplines that is highly motivated and ready for this effort to begin. Initially, there will be limiting factors as outlined below in areas for exploration, but there exists the opportunity to package what exists and leverage it to greatly boost research in this area. It is also suggested that the opportunity exists to employ industry academic partnerships to fully engage the expertise and creativity of industrial partners in idea generation and testing that will benefit all sectors.
Some of the immediate needs in QSP include the following areas thought to be ripe for exploration via collaborative/integrative centers: 1) the quantitative characterization of drug targets; 2) factors affecting patient response variability; 3) better animal and tissue models; 4) re-connection of medicinal chemistry and tissue pharmacology; 5) information exchange formats extending from chemistry to electronic medical records; 6) better computational models with pharmacological mechanisms; 7) development of systems approaches to failure analysis; 8) defining of core competencies for training in QSP; 9) development of pedagogical resources; 10) novel formats for training, including that for established investigators; and 11) novel academic industry partnerships covering research and training.
Potential impact of Common Fund investment: The primary results of a successful QSP centers program are expected to include: 1) major advances in the fundamental understanding of how drugs act; 2) more direct translation of discoveries made in cells to patients; 3) improved biomarkers that assay directly the effects of drugs in tissues and patients; 4) a stronger scientific basis for multi-drug therapy and re-purposing of existing drugs and drug candidates abandoned in development; 5) a more rational basis for polypharmacy and predicting drug-drug interactions; 6) a higher success rate for new drug candidates successfully entering the market place with acceptable toxicities and predictive variability among patient types; 7) higher rates of success of clinical trials; and 8) a stronger investigator pool for academia and industry and a new generation of leaders in academic and industrial pharmacology.