Clinical Research Bridging the Gap between Basic Science and Improved Human Health FASEB Clinical Research Subcommittee

What Is Clinical Research? Research conducted on humans or human tissues that makes use of patient data. Includes study of disease mechanisms, therapeutic interventions, epidemiology, and clinical trials. Aimed at understanding human disease and improving human health. Interaction between researchers and patient data is a key feature. Definitions of Clinical Research

Why is Clinical Research Important? Enhances our understanding of human physiology and pathophysiology. Translates basic research into medical care. Informs and drives basic research. Improves diagnostic tools and preventive care. Improves human health!

What Can Clinical Research Accomplish? Research in human physiology and pathophysiology translates basic research into knowledge of disease mechanisms and medical therapeutics. Clinical trials establish safety and efficacy of new interventions. Epidemiological and behavioral research identify high risk populations with potential to benefit from prevention, early detection, or therapeutic intervention. Outcomes and health services research assess the health impact and cost-effectiveness of interventions.

Physiological Research Carefully controlled studies in patients or normal subjects that are intended to understand basic physiologic mechanisms and their disruption in human disease. Translation of basic research findings (in vitro and preclinical animal investigation) to human subjects to confirm the human relevance of proposed disease mechanisms, which will inform scientifically targeted medical therapeutics. This work is usually done through General Clinical Research Centers (GCRC) and informs clinical trials.

Clinical Trials Research that prospectively assigns human subjects to intervention and concurrent comparison/control groups to study the cause-and-effect relationship between a medical intervention and a health outcome (International Committee of Medical Journal Editors). http://clinicaltrials.gov/ct/info/whatis#types

Clinical Trial Phases Phase I trials: First-time test of intervention in a small group of people (20-80) to evaluate safety, determine appropriate dosage, and identify side effects. Phase II trials: Intervention given to a larger group (100-300) to evaluate effectiveness and safety. Phase III trials: Intervention given to large groups (1,000-3,000) to confirm effectiveness, monitor side effects, compare to other treatments, and collect information that will allow it to be used safely. Phase IV trials: Post marketing studies determine additional information including risks, benefits, and optimal use of an intervention.

Population Research Epidemiology and behavioral research to identify high risk populations with potential to benefit from prevention, early detection, or intervention of established disease processes. Outcomes and health services research to assess the health impact and cost-effectiveness of an effective intervention in a population or community setting.

Basic and Clinical Research are Interdependent Improved Health Basic and clinical research do not operate independently. Basic research findings inform the development of clinical research studies and data from clinical research studies improve our understanding of human health and disease. Ultimately, this results in improvements in medical treatment, diagnostics, and preventive care. In turn, data collected in clinical settings (including through population-based research) drive the development of clinical and basic research questions and hypotheses. Translation from basic science to human studies Translation of new knowledge into clinical practice Adapted from Sung et al. (2003) JAMA, 289, 1278-89. Copyright © (2003) American Medical Association. All Rights reserved.

Linking HIV to AIDS Basic research into DNA, viruses, and retroviruses paved the way for the identification of the first human retrovirus in cancer patients. Clinical studies showed that cancer-causing retroviruses exert similar effects to AIDS on the human immune system. This helped scientists to identify HIV, a retrovirus in the same family as the cancer-causing retroviruses, as the one responsible for the development of AIDS. http://opa.faseb.org/pdf/Finding_Chinks.pdf

Helping Newborns Breathe Tens of thousands of babies died annually from a mysterious respiratory ailment. Clinical investigators characterized the patients and studied infant respiration and human lung physiology. Separately, basic studies of surface tension and pulmonary physiology allowed researchers to identify and characterize pulmonary surfactant. With this information in mind, clinical and basic scientists determined that the deaths were due to a lack of surfactant, which caused the alveoli, or air sacs in the lungs, to collapse. Treatments were then developed in the lab and tested in and applied to patients with great clinical success. http://opa.faseb.org/pdf/babies_bubbles.pdf

Combating Breast Cancer Basic research findings demonstrated the anti-tumor effects of tamoxifen in lab animals. Clinical researchers showed that tamoxifen shrank breast tumors in afflicted women and reduced the risk of tumor recurrence. Clinical researchers also demonstrated that healthy women treated with tamoxifen were less likely to develop breast cancer. Tamoxifen is now widely used as a breast cancer treatment and preventive. http://opa.faseb.org/pdf/Breast_Cancer_Breakthru.pdf

Who Funds Clinical Research? Federal Government National Institutes of Health Department of Veterans Affairs Centers for Disease Control and Prevention Agency for Health Care Research and Quality Department of Defense Private Organizations Foundations and other not-for-profits Industry *State and local governments also fund clinical research*

Sponsors of Biomedical Research (Basic and Clinical) This graphs shows the source of funding for all biomedical research from 1994 through 2003. The data were compiled from public and private sources, and all figures were adjusted for inflation using the biomedical research and development price index (BRDPI). According to this analysis, total funding for biomedical research increased from $37.1 billion in 1994 to $94.3 billion in 2003. Industry is the largest and NIH is the second largest supporter of biomedical research. Private funding makes up only a small portion of total funding for biomedical research. Moses et al. (2005) JAMA, 294, 1333-42 Copyright © (2003) American Medical Association. All Rights reserved

National Institutes of Health NIH Mission: Science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability. NIH is a major sponsor of clinical research. Clinical Research Initiatives: NIH Roadmap: Reengineering the Clinical Research Enterprise Clinical and Translational Science Awards NIH Director, Dr. Elias Zerhouni

NIH Spending on Clinical Research NIH Budget FY 2003-2008 Fiscal Year Spending ($Billions) Non-Clinical Research Other Clinical Research Clinical Trials 0.0 5.0 10.0 15.0 20.0 25.0 30.0 2003 2004 2005 2006 2007* 2008* * Estimated Funding These data show NIH funding for clinical trials, other clinical research, and all other (non-clinical) research from 2003 through 2008. Figures for 2007 and 2008 are estimated. Funding for clinical research (including clinical trials) as a percentage of overall research spending has remained fairly stable over this time period. Year Total NIH Total Clinical Research (CR) Clinical Trials Other Clinical (Total CR-Clinical Trials) Spending (Total NIH-Total CR) 2003 27.0 8.0 2.7 5.3 19.0 2004 27.9 8.5 2.9 5.6 19.4 2005 28.5 8.7 5.9 19.8 2006 28.3 8.8 2.8 6.0 19.5 2007 28.4 6.1 19.6 2008 28.6 http://officeofbudget.od.nih.gov/FY07/Overview.pdf http://www.nih.gov/about/almanac/appropriations/part2.htm http://www.nih.gov/news/fundingresearchareas.htm

NIH Spending on Clinical Research Non-Clinical Research $19.83 Billion (69.3%) Other Clinical Research $6.03 Billion (21.1%) Clinical Trials $2.76 Billion (9.6%) *Estimated These data show estimated NIH funding for clinical trials, other clinical research, and non-clinical research for FY 2008. NIH spends approximately 30% of its research budget on clinical research. Year Total NIH Total Clinical Research Clinical Trials Other Clinical Research (Total CR-Clinical Trials) All Other Spending (Total NIH-Total CR) 2008 28.6 8.8 2.7 6.0 19.8 http://officeofbudget.od.nih.gov/FY07/Overview.pdf http://www.nih.gov/news/fundingresearchareas.htm

Reengineering the Clinical Research Enterprise Improve medical diagnostics and treatment. Enhance access to and sharing of data through integrated clinical research networks. Enhance clinical outcomes assessment by developing a computerized system to collect and store patient-reported outcomes data. http://nihroadmap.nih.gov/clinicalresearch/

Reengineering the Clinical Research Enterprise Expand and diversify the clinical research workforce by optimizing training and career development programs. Harmonize federal requirements regarding conduct of clinical research to facilitate compliance with regulations and policies. Promote translational research by improving clinical research infrastructure (Clinical and Translational Science Award program). http://nihroadmap.nih.gov/clinicalresearch/

Funding for the NIH Roadmap FY 2007* Roadmap Funding $414.1 Million Total NIH Funding $28.4 Billion Non-Roadmap Roadmap 98.3% 1.5% Reengineering Clinical Research Research Teams of the Future New Pathways to Discovery 36.4% 20.7% 42.9% 98.5% *Estimated funding The NIH Roadmap was created to provide “a framework of the priorities NIH as a whole must address in order to optimize its entire research portfolio.” In 2007, it is expected that 1.5% of the total NIH budget will be spent on the Roadmap programs. Of the Roadmap funding, 36.4% will be directed at “Reengineering the Clinical Research Enterprise” programs. Other components of the Roadmap include “New Pathways to Discovery,” which aims to expand our understanding of biological systems and develop new research tools, and “Research Teams of the Future,” which will encourage high-risk and interdisciplinary research and public-private partnerships.   Millions of $ Percent Total NIH Funding 28,389.10 Non-Roadmap 27,975.00 98.5* Roadmap 414.1 1.5* New Pathways to Discovery 177.6 42.9** Research Teams of the Future 85.6 20.7** Reengineering Clinical Research 150.9 36.4** http://officeofbudget.od.nih.gov/FY07/Overview.pdf *Percent of Total NIH funding **Percent of Roadmap funding

Clinical and Translational Science Awards Transforms academic health centers into definable academic homes for clinical and translational science, which work together to improve the conduct of clinical research. Subsumes some General Clinical Research Centers (GCRC). 12 academic health centers participating. 52 planning grants. Funded from existing clinical research programs and Roadmap dollars. No funds are taken from basic research. http://ctsaweb.org/about.html

Department of Veterans Affairs Total FY 2007 R&D budget = $818M Medical and Prosthetics Research program budget = $412M Aimed at improving health care for veterans through research on relevant illnesses and injuries. Four major R&D areas: Clinical Science Research and Development Service = $72M Cooperative Research Program (Clinical Trials) Health Services Research and Development Service = $68M Rehabilitation Research and Development Service = $54M Biomedical Laboratory Research and Development Service = $249M http://www.aaas.org/spp/rd/va08p.htm

Department of Veterans Affairs 75% of supported researchers are clinician scientists. More than half of all VA research is for investigator-initiated projects. All R&D investment is intramural. http://www.aaas.org/spp/rd/va08p.htm

Other Federal Sponsors of Clinical Research Agency for Healthcare Research and Quality Clinical practice, patient safety, health IT, primary and priority populations care, and evidence-based medicine. Centers for Disease Control and Prevention Infectious disease, disability, environmental health, health statistics. Department of Defense Congressional Special Interest Research Programs: Includes research on breast, prostate, and ovarian cancer and other diseases. Deployment Health-Related Research: Research on conditions affecting deployed or previously deployed military (e.g., PTSD). Defense Advanced Research Projects Agency: Includes funding for applied biological research (e.g., effects of bioagent exposure).

Private Sponsors of Clinical Research Not-for-profits Foundations, voluntary health organizations, and research institutes. Examples: Bill and Melinda Gates Foundation, Burroughs-Wellcome Foundation, Juvenile Diabetes Research Foundation. Industry Pharmaceutical, biotechnology, and medical device firms. Pharmaceutical Research and Manufacturers of America (PhRMA). Biotechnology Industry Organization (BIO).

Pharmaceutical Industry Funding for Clinical and Basic Research Type of Research 1994 2003 Prehuman and Preclinical 57% 32% Phase 1-3 28% 41% This table shows pharmaceutical industry research and development (R&D) spending on prehuman and preclinical research (i.e., basic research), Phase 1-3 clinical trials, and Phase 4 clinical trials as a percentage of total pharmaceutical industry R&D spending. Industry spending on basic research has dropped from 57% to 32% of total industry R&D spending from 1994 to 2003, while funding for clinical research has increased. Phase 4 5% 11% Adapted from Moses et al. (2005) JAMA, 294, 1333-42 Copyright © (2003) American Medical Association. All Rights reserved

How is Clinical Research Regulated? Local Institutional Review Boards Conducts initial review of research proposal. Ensures participants are not exposed to unreasonable risks and that they give informed consent. Conducts continuing review of approved research to ensure that human-subject protections remain in force. Food and Drug Administration Regulates approval process for medical therapies and devices.

Challenges Faced By Clinical Researchers Difficulty balancing patient care and research responsibilities. Expensive medical training; lower salaries compared to private clinicians. Long training time compared to medical school peers. Burdensome regulations and paperwork. Insufficient mentoring due to competing pressures. Low success rate for clinical R01s.

Addressing the Challenges Assess clinical research career development awards to optimize retention of clinical researchers. Promote effective mentoring by senior clinical researchers. Implement loan forgiveness programs to boost retention in the research track. Streamline, standardize, and simplify regulatory requirements. Include reasonable “protected time” requirements in grants to ensure sufficient time for research. Ensure adequate representation of clinical researchers on review panels for clinical research grants. For additional information: Kotchen et al. (2006) J. Investigative Medicine; Murillo et al. (2006) Academic Medicine; Sung et al. (2003) JAMA.

Why Improve the Landscape for Clinical Research? Enhance recruitment and retention of clinical researchers. Prevent future shortage of clinical researchers. Optimize bench to bedside translation of research. Drive basic science discoveries. Improve human health!

Resources: Clinical Research Organizations Association of American Medical Colleges Association for Patient-Oriented Research Clinical Research Forum Health Research Alliance Institute of Medicine: Clinical Research Roundtable National Institutes of Health

Resources: Clinical Research Reports The NIH Director’s Panel on Clinical Research Report to the Advisory Committee to the NIH Director (The Nathan Report,1997, NIH). The Physician Scientist: Career Issues and Challenges at the Year 2000 (Zemlo et al., 2000, FASEB Journal). Central Challenges Facing the Clinical Research Enterprise (Sung et al., 2005, JAMA). Meeting the Challenges Facing Clinical Research: Solutions Proposed by Leaders of Medical Specialty and Clinical Research Societies (Murillo et al., 2006, Academic Medicine) Outcomes of National Institutes of Health Peer Review of Clinical Grant Applications (Kotchen et al., 2006, J. Investigative Medicine). Promoting Translational and Clinical Science: The Critical Role of Medical Schools and Teaching Hospitals (2006, AAMC). New Physician-Investigators Receiving National Institutes of Health Research Project Grants (Dickler et al., 2007, JAMA).

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