Clinical Advisory Subcommittee of the National Advisory General Medical Sciences Council

Location:
NIH, Bethesda, Maryland

Start Date: 4/12/1999 8:00 AM

End Date: 4/12/1999 3:00 PM

Introduction

A subcommittee of the National Advisory General Medical Sciences Council (NAGMSC) was convened for a one-day meeting on April 12, 1999 to consider needs, opportunities, and obstacles in the clinically relevant scientific areas supported by NIGMS. Chairing the meeting was Dr. Naji Abumrad, Professor of Surgery, North Shore University Hospital. The subcommittee included 11 scientists representing the fields of anesthesiology, clinical pharmacology, and trauma and burn injury. The group also included NAGMSC members Dr. Steven Paul and Dr. Robert Pozos. Topics for discussion were not limited, but the committee was asked to focus on issues specific to research, since training issues have been the focus of a number of recent meetings. Questionsprovided to the participants prior to the meeting are included in this report. Major themes that emerged from the meeting have been presented in the Executive Summarysection of this report; a more detailed presentation of the issues can be found in the Discussionsection. One message that emerged from the meeting is that the clinically relevant communities supported by NIGMS require a greater awareness of the recent NIGMS initiatives.

Executive Summary

Research in anesthesiology, clinical pharmacology, and trauma and burn injury is unique within NIGMS because of the clinical focus inherent to these areas of study. These approaches raise special needs that can be addressed by the Institute. Without question, these clinically relevant areas have broad relevance to economic and social issues, and to human health. Within NIGMS they comprise a valuable and unique source of basic science and study of fundamental biological mechanisms. However, to a much larger degree than most other segments of NIGMS-sponsored research, investigators in these three areas have a responsibility not only to acquire knowledge but also to apply the information generated to solving human health problems.

Clinical research prompts a test of our understanding of basic biological mechanisms, and provides clues to the missing pieces. There is a timely need to support more clinical research to test and validate hypotheses generated by the mounting body of information provided by basic biomedical research. There is a sense that for these clinically oriented areas of research, specialized centers with M.D.s and Ph.D.s housed under one roof will be required for the effective translation of basic research findings into clinical advances. Thought should also be given to other mechanisms such as creating networks among investigators doing basic clinical science, particularly in research centers, to stimulate interactions. Another approach could be to provide the means for investigations of mechanistic questions in clinical science to accompany conduct of large population clinical trials . Finally, another direction could be to expand the General Clinical Research Center (GCRC) infrastructure to cover more of the clinical research performed by these communities . Given that NIGMS only supports part of the spectrum of clinical research, NIGMS staff should work to forge relationships with other institutes and agencies more oriented to patient care. This would ensure continuity of research support for clinical research in these three areas.

These research recommendations presume that an adequate number of well-trained and interested scientists from diverse backgrounds will be available. Thus, it is impossible to entirely separate any discussion of research needs from issues related to training. Strong support was expressed for the existing postdoctoral training grant (T32) programs, and for the mentored clinical scientist awards (K08) program now offered by NIGMS. The group expressed a strong feeling that training issues are twofold: first, physicians must be trained in basic, hypothesis-driven science , and second, those with Ph.D. degrees need to acquire a greater sense of clinical reality . There is a need to find mechanisms to make clinical research more attractive as a career path to medical students and residents. One approach could be through debt relief and/or special educational efforts in medical schools to highlight opportunities in clinical research. It is also critical to attract more Ph.D. scientists to problems in clinically relevant research. Greater involvement of scientists trained in cutting-edge molecular and integrative sciences will be crucial to the success of clinical research regardless of the degree of the investigator. It is not clear that Ph.D. scientists are aware of the opportunities to bring their skills and expertise to bear on clinically relevant problems or of the opportunities for funding that exist to support such efforts. A broad issue relevant to all three areas is the need to promote interactions between M.D. and Ph.D. scientists . The group cited existing interactions between M.D. and Ph.D. scientists as being surprisingly limited, and expressed that it would be helpful if mechanisms were created whereby collaborating Ph.D. and M.D. scientists can receive equal credit when submitting proposals jointly or as parts of larger awards.

Another area of concern voiced by the group is the need for common models of human injury and of pain mechanisms . NIGMS could enhance research progress by offering some sort of infrastructure to test, standardize, and authenticate animal models , and then to assure such models are widely available. Along these lines, the fact that NIGMS, as well as the entire NIH, is putting significant resources into fostering the study of model organisms (for example, the Mouse Initiative) was well received as a crucial development. The group also felt that critically ill patients in the intensive care unit (ICU) provide one common focal point for all three clinically relevant areas supported by NIGMS, since each of these areas involves the study of individuals whose normal physiology is severely perturbed. Important fundamental issues remain unresolved as to how physiological systems are inter-regulated in normal and perturbed states, as well as which underlying mechanisms control the critically ill patient's ability to recover. Importantly, these states are greatly affected by age, sex, and physical condition. They also involve important considerations regarding inter-individual variation in response to therapeutic drugs. A need exists to better understand underlying pain mechanisms and strategies for pain management. In addition, there are a wealth of unexplored "systems biology"-related research questions in these areas.

An overwhelming response of the subcommittee was that many current directions being fostered by NIGMS are important directions for the represented clinical communities, including: (a) the emphasis on complex systems and integrative science, (b) the emphasis on improving the quantitative aspects of biological science, and (c) the recent pharmacogenetics initiatives aiming to link the products of genomic science to therapeutics. However, it was strongly felt that NIGMS should increase the awareness of the clinical investigator communities to the various initiatives sponsored by the Institute. Thus, the subcommittee urged that NIGMS staff further emphasize communication of its new initiatives to heighten awareness of opportunities for clinical investigators in these areas. In this regard, consideration should be given to writing future NIGMS announcements such that they more clearly include clinical investigators.

Discussion

Research Frontiers

A major challenge facing investigators in anesthesiology, clinical pharmacology, and trauma and burn injury is how to apply the knowledge, insight, and reagents and materials derived from modern biology--especially genomics science--to clinical research. The precipitous rise of genomic science prompts important questions about inter-individual physiologic variability. Another area of emerging opportunity is polygenic diseases. This is an area ripe for new creative approaches to applying the products of genomic science to the clinical arena. In general, the need to devise strategies for providing individual-specific treatment is an underlying theme for all three areas. Approaches toward achieving this goal include pharmacogenetic/pharmacogenomic studies aiming to link phenotypic differences to genotype, and investigations of the alteration in cellular and systems responses that can be linked to patient state (age, gender, and pathological condition). The opportunities to investigate complex systems also means that there are useful advances to be harvested from biophysics, chemistry, biochemistry, structural biology, mathematics, and computer science.

Anesthesiology: The molecular mechanisms of anesthetic action remain elusive, raising several important research issues. Research in perioperative pain and pain management, including inter-individual variation of pain perception and response to analgesics, have come to the forefront in the areas of anesthesiology and trauma and burn injury. Another research frontier is the goal to understand the mechanisms of nerve injury caused by local anesthesia. There is also a need in the research community for greater emphasis on using structural biology as a tool to understand anesthetic action.

Clinical Pharmacology: An emerging area of importance in clinical pharmacology is the need to add mechanistic-based studies in pharmacology to clinical trials of drugs in large populations. One possible approach to addressing this need could be to award supplements to large clinical trials, to support concurrent pharmacological studies and to develop a network of such studies. Archiving of DNA to allow follow-up genotype/phenotype studies is another consideration. As a corollary, it might be possible for investigators to partner with industry to run mechanistic studies alongside clinical trials. Other frontier areas include the study of regulated versus dysregulated stress responses, the search for improved biomarkers for toxicity, study of adverse drug reactions, studies in disease progression modeling, and alternative medicine. There is also a need to address the issue of traditional drug development methodologies, as new therapies may require modified, or even novel, approaches to evaluating efficacy and appropriate usage.

Trauma and Burn Injury: Frontier areas in trauma and burn injury include research on the effect of gender and age on the treatment of trauma and sepsis, and inter-individual variation in response to injury. The group recommended that additional support should be made available for investigating appropriate dosing regimens for experimental therapeutics (biological response modifiers, for example) with novel physiologic targets. Some existing drugs approved for other indications may have additional biological effects that have a benefit in the treatment of trauma. Thus, the group recommended that it would be worthwhile to evaluate such approved drugs for their potential in trauma treatment. A major leading-edge area involves studies aiming to improve the understanding of what controls the ability of both cells and biological systems to recover, and how this process may be suppressed in injury, as well as why it deteriorates over time. One participant stated, "NIGMS has an unparalleled opportunity to promote the integration of genomics, pharmacogenetics, the biology of inflammation, and the care of the injured patient." There is also a great need for developing standards for models of injury. The current plethora of models and protocols of uncertain relevance to humans is a serious obstacle for these fields. One member stated that these models divert attention toward species-specific and model-specific phenomena, and added that "conferences and workshops aimed at this area may represent sound investments."

A common theme for anesthesiology, clinical pharmacology, and trauma and burn injury is the fact that these areas all may deal with humans harboring a seriously disturbed physiology. These three areas can all converge within the intensive care unit (ICU), centering upon the common question of how biological systems are regulated and dysregulated. The altered physiology of patients within the ICU (including those in the perioperative period) is of general common interest to the three clinical communities served by NIGMS. Another prevalent theme is that given the current widespread usage of transgenic and knockout mouse strains, there is a great need for more in-depth basic pharmacological and physiological studies of these genetically altered mice in order to understand, standardize, and enhance the information obtained.

Clinical Research Needs

A substantial challenge for clinical research is finding the means to bring the "new biology"--particularly that derived from genomic science--to clinical science, and to translate that research into patient care. Scientists in clinically relevant sciences have a special responsibility to apply knowledge that is accumulating from recent research advances. This will require increasing the number of M.D.s trained in basic science, attracting the brightest Ph.D.s trained in relevant sciences, and promoting an increased "synergy between laboratory and clinical science." Clinical research is needed not only for its importance in translating fundamental discoveries into improvements in human health, but also to contribute toward an understanding of basic biological mechanisms. Developing technologies will allow increasingly sophisticated questions to be addressed. There is also a need for studies that can improve clinical research methodologies. Opportunities for clinical research capitalizing on modern scientific accomplishments need to be expanded. There are a wealth of biomedical research discoveries waiting to be tested in the clinical arena.

Beyond the scientific issues, the administrative support required to advance these fields should be strengthened to optimize the entry, training, and retention of the next generation of research scientists addressing clinically relevant problems. For example, debt loads typically carried by new physicians are a strong disincentive to entering research careers where compensation is much lower than in clinical practice. The group stated that it would be desirable to provide a debt relief mechanism for clinicians; such an approach would go a long way toward removing a significant barrier to physicians entering research. Furthermore, the clinical scientist must spend increasing amounts of his or her time performing clinical duties, in order to recover their salaries. Thus, efforts to maintain adequate salary compensation on career awards for academic physicians will have the effect of increasing release time for research; this is true for senior investigators as well as junior scientists. Well-developed career paths are necessary for clinical scientists regardless of the degree held. Ph.D.s working in clinical departments must obtain their salary through grants; the lack of security for these experienced scientists provides a disincentive to Ph.D.s being attracted to clinical research.

Certain infrastructure needs also need to be addressed. Since many of the research issues are very broad in scope, and because in some cases obtaining a critical mass of scientists and populations for some clinical investigations may be difficult, every effort to promote and enhance multi-institutional cooperative efforts should be made. Establishment of core facilities, such as for biostatistics for example, would be beneficial, as might expanding the GCRC concept and associated infrastructure to include under-served areas such as critical care and surgical research. As with the care of injured patients, research in this area is multidisciplinary, raising additional problems such as communication and identifying potential collaborators with needed expertise. Since such endeavors often require that efforts on a project be multi-institutional, creating a network of existing centers could stimulate interactions in this area.

Since many current medical practices are based on anecdotal observations, the group recommended that more attention be paid to evidence-based medicine in the trauma and burn injury area. However, as many of these issues are beyond the scope of the NIGMS mission, there is a need to identify programs in other funding agencies more oriented to patient care. There should be partnering with other institutes or federal agencies to ensure that necessary work is supported.

M.D.-Ph.D Interactions

Revolutionary scientific advances require an environment where creative ideas can flourish. Clinical research is an area where maximal interactions between M.D. and Ph.D. researchers are important for progress. Interactions and collaborations between M.D. and Ph.D. scientists are much more limited in numbers and depth than are optimal. One solution might be to consider creating "Specialized Centers of Excellence" (forming translational research teams of M.D.s and Ph.D.s placed under one roof with an emphasis on integrated approaches) and forming a network of these centers. To stimulate necessary interactions, there is also a need for proper attribution of credit and recognition for PIs of subprojects on large grants and in other collaborative arrangements. Currently, many departments only give credit to the overall PI, providing a disincentive to investigators to participate in collaborative award mechanisms such as program projects and center grants that are crucial to translational research. Another possible approach might be to expand the use of interactive RO1 awards (http://grants.nih.gov/grants/funding/irpg.htm) to promote interactions between clinical and laboratory scientists. In such an approach, Ph.D. and M.D. scientists can submit proposals jointly, receiving equal credit. Finally, Ph.D. scientists may be unaware of the relevance of their knowledge and skills to clinical research problems, or of the opportunities for support in these areas. Similar to existing mechanisms training M.D. scientists in basic science, "parallel mechanisms to allow basic scientists formal exposure to clinical medicine to further increase basic clinical interactions may be desirable."

Training Issues

Although the focus of this meeting was research, training issues still surfaced in the discussion. The group noted that the postdoctoral institutional training grants (T32s) and the mentored clinical scientist development awards (K08s) offered by NIGMS are valuable to researchers in clinically relevant areas, and continued emphasis and support for these awards was considered important. The group recognized a need to attract more talented M.D. and Ph.D. scientists to clinically relevant endeavors. A major problem for clinical pharmacology is its limited visibility as a discipline to medical students and residents; this adversely affects recruiting researchers to this area. There is a sense generally that awareness of the opportunities in clinical research among medical students and residents is low and needs to be heightened. Infrastructure needs, perhaps more so in the clinically relevant disciplines than others, affect the entry and training of the next generation of research scientists. In this regard, an additional effect of the aforementioned centers of excellence might be the multidisciplinary, interactive environment that they foster, which could aid the attraction and development of both M.D. and Ph.D. scientists.

Communication Issues

As noted above, the group stated a need for greater communication of the opportunities for M.D. and Ph.D. scientists to participate in clinically relevant research, to improve the interactions of M.D.-Ph.D. scientists, and to improve the coordination and collaborations between research groups. Many of the Institute's recent initiatives were considered to be important research directions for these clinically relevant areas, but this may not be widely perceived by the clinical communities. For example, the Institute's efforts to support complex systems and integrative and quantitative science were viewed favorably as an important adjunct to research in the clinical sciences. The need remains for greater linkage of the quantitative sciences to problems in human pathophysiology and pharmacology, and there should be an emphasis on integrative approaches and investigations of complex systems. A major issue for all three clinically relevant areas was the inter-individual variability in response to drugs and treatments, and the recently announced NIGMS initiatives on pharmacogenetics were viewed as a very positive development. These factors led the committee to recommend that NIGMS staff make special efforts to write Institute initiatives such that relevance to clinical investigation is clear and make a greater effort to alert clinical investigators to new and existing opportunities.

To convey comments on this report, contact Dr. Michael Rogers.

Questions

(distributed to subcommittee members prior to meeting)

We ask that you think about and respond to the first three general questions posed below to form the substance of the bullets that we have asked you to prepare. These are the identical questions that were posed to the advisory groups that were held last year and are meant to stimulate your thinking as you prepare for our meeting.

General:

  1. Are there important scientific questions which need to be addressed that require a special effort beyond the normal funding process? What are the major scientific developments that are likely to influence the future of research in your field, such as genomics, transgenic organisms, combinatorial chemistry, and high-throughput screening technologies? What research efforts are called for to address the challenges and opportunities that these developments pose? What special efforts are required to promote the synergism between laboratory science and clinical discovery? What opportunities might be opened up by the emergence of quantitative and integrative approaches to the study of basic biological processes, such as metabolism, regulation, and physiological response to drugs or injury?
  2. Are there significant obstacles (model systems, databases, instrumentation, manpower, funding mechanisms, other resources) which limit these opportunities?
  3. Are there specific initiatives that NIGMS should undertake to address new opportunities?

The following are some additional questions that are of current interest to staff. We would appreciate your feedback on any of the questions you may wish to address, but they are not meant to necessarily be a focus area for our discussion. Indeed, please do not feel in anyway limited by any of the questions posed on this list, but feel free to bring up any other points you would like to see addressed.

Program Related:

  1. What are the opportunities in pain/pain management research relative to the field of anesthesia?
  2. Is there an NIGMS-relevant, basic science base in clinical pharmacology that needs to be developed in any particular area, such as the problem of adverse drug reactions?
  3. Would there be a substantial benefit to creating a network connecting the NIGMS supported centers in trauma and burn injury (for example, to foster exchange of data, to standardize animal models or standards of clinical care for human studies, or to allow transfer of research fellows)?
  4. There is considerable evidence of a bidirectional link between an individual's physiology and their psychological state (which includes cognitive and emotional components). Do opportunities exist to examine the mechanistic basis for such links on the response to anesthesia/analgesia, therapeutics, and trauma and burn injury?
  5. What are the common themes for the three clinically relevant areas of anesthesiology, clinical pharmacology, and trauma and burn injury?
  6. What are the long term future directions for research in the areas of anesthesiology, clinical pharmacology, and trauma and burn injury?

NIGMS Initiatives

Roster

Chairperson:

ABUMRAD, Naji N., M.D.
Professor of Surgery
North Shore Health System
North Shore University Hospital
300 Community Drive, Manhasset
New York, New York 11030
Phone: 516-562-2870
Fax: 516-562-4821
Email: nabumrad@nshs.edu

Participants:

ABERNETHY, Darrell R., M.D., Ph.D.
Chief, Laboratory of Clinical Investigation
National Institute on Aging
Gerontology Research Center
5600 Nathan Shock Drive
Baltimore, Maryland 21224-6825
Phone: 410-558-8611
Fax: 410-558-8318
Email: abernethyd@grc.nia.nih.gov

BUCHMAN, Timothy G., M.D., Ph.D.
Professor
School of Medicine
Washington University
660 South Euclid Avenue Box 8109
St. Louis, Missouri 63110
Phone: 314-362-5297
Fax: 314-362-5743
Email: buchman@msnotes.wustl.edu

CHAUDRY, Irshad H., Ph.D.
Professor
Department of Surgery
Brown University, Rhode Island Hospital
593 Eddy Street, Center for Surgical Res.
Providence, Rhode Island 02903
Phone: 401-444-5582
Fax: 401-444-3278
Email: ichaudry@lifespan.org

EISENACH, James C., M.D.
Professor of Anesthesiology
School of Medicine
Wake Forest University
Medical Center Boulevard
Winston-Salem, North Carolina 27157-1009
Phone: 336-716-4182
Fax: 336-716-8190
Email: eisenach@bgsm.edu

FIRESTONE, Leonard L., M.D.
Safar Professor and Chairman
Department of Anesthesiology/CCM
University of Pittsburgh
A1/305 Scaife Hall
Pittsburgh, Pennsylvania 15261
Phone: 412-648-9624
Fax: 412-648-1887
Email: firestone@smtp.anes.upmc.edu

JONES, Keith A., M.D.
Associate Director
Department of Anesthesiology
Mayo Foundation Rochester
200 First Street, N.W.
Rochester, Minnesota 55905
Phone: 507-255-4288
Fax: 507-255-7300
Email: kjones@mayo.edu

NANNEY, Lillian B., Ph.D.
Professor
Department of Surgery, Research Lab.
Vanderbilt University, S-221 Medical Center North
21st Avenue South & Garland Avenue
Nashville, Tennessee 37332
Phone: 615-322-7265
Fax: 615-343-2050
Email: lillian.nanney@mcmail.vanderbilt.edu

RATAIN, Mark J., M.D.
Professor of Medicine
Department of Medicine
University of Chicago
5841 S. Maryland Avenue, MC 2115
Chicago, Illinois 60637-6300
Phone: 773-702-4400
Fax: 773-702-9699
Email: mjratain@mcis.bsd.uchicago.edu

RODEN, Dan M., M.D.
Director
Division of Clinical Pharmacology
Vanderbilt University Medical Center
315 Medical Research Bldg. II
Nashville, Tennessee 37332-6300
Phone: 615-322-0067
Fax: 615-343-4522
Email: dan.roden@mcmail.vanderbilt.edu

SCHWINN, Debra A., M.D.
Professor
Department of Anesthesiology
Duke University Medical Center
Post Office Box 3094
Durham, North Carolina 27710
Phone: 919-681-4781
Fax: 919-681-4776
Email: schwi001@mc.duke.edu

TOMPKINS, Ronald G., M.D., Sc.D.
Chief
Department of Surgery Service
Massachusetts General Hospital
55 Fruit Street, General Hospital Corp.
Boston, Massachusetts 02114-2696
Phone: 617-726-3447
Fax: 617-367-8936
Email: rtompkins@partners.org

Council Members:

PAUL, Steven M., M.D.
Vice President
Therapeutic Area Discovery Research
Lilly Research Laboratories
Lilly Corporate Center
355 E. Merrill Street
Indianapolis, Indiana 46285-0530
Phone: 317-276-1277
Fax: 317-276-1125
Email: paul_steven_m@lilly.com

POZOS, Robert S., Ph.D.
Assistant Dean
College of Science
San Diego State University
5500 Campanille Drive
San Diego, California 92182-4616
Phone: 619-594-1204
Fax: 619-594-3590
Email: bpozos@sciences.sdsu.edu