Opportunities and Challenges in Pediatric Clinical Research1

Inese Z. Beitins

National Center for Research Resources, National Institutes of Health, Bethesda, Maryland 20892

Address correspondence and requests for reprints to: Inese Z. Beitins, M.D., FRCP(C), National Center for Research Resources, General Clinical Research Center Program/National Institutes of Health, One Rockledge Center, Room 6030, 6705 Rockledge Drive, MSC 7965, Bethesda, Maryland 20892-7965.


    Introduction
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 Introduction
 National Institutes of Health...
 General Clinical Research...
 Current Trends in Clinical...
 Conclusion
 References
 
ALMOST 100 YEARS ago, Sir William Osler gave voice to a goal. "To wrest from nature the secrets which have perplexed philosophers in all ages, to track to the sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease — these are our ambitions" (1). Sir William Osler brought to medicine the art of careful and detailed observation of the pathology and progress of disease. He used this and the newly emerging tools and technologies of laboratory chemistry to formulate testable hypotheses. Following this example, many physicians in academic institutions, in concert with basic scientists, established the fields of medical science and clinical investigation and ushered in a new era that revolutionized not only medical practice but also medical education. Clinical scientists versed in bedside practice as well as the knowledge and techniques of basic sciences were now interposed between the basic scientists and the community physicians. Gradually, the medicaments and treatments based on faith and folklore were largely replaced by the products of medical research and investigation. Subsequent discoveries and consequent improvement in health have been truly amazing.

The first clinical research hospital entirely dedicated to medical experimentation and discoveries opened its doors at the Rockefeller University (New York, NY) in 1910. To further advance clinical investigation, Frederick T. Gates persuaded Mr. Rockefeller that, "... medicine could hardly hope to become a science until it should be endowed and qualified men could give themselves to uninterrupted study and investigation on ample salary, entirely independent of practice" (2). This trend was rapidly emulated by other academic centers, and in 1912 John Howland became the first full-time head of Pediatrics at the Johns Hopkins Hospital (Baltimore, MD).

The practice of allowing medical scientists to devote their time and energies to clinical investigation on a full-time basis led to monumental achievements. Smallpox, diphtheria, and tetanus, infections that had plagued populations for centuries, are no longer seen. Polio, measles, whooping cough, and rubella are fast disappearing. Improved sanitation has prevented outbreaks of such dreaded epidemics as typhoid fever and salmonella. The metabolic disturbances secondary to such gastrointestinal disorders led to dehydration, electrolyte imbalance and acidosis – conditions that in themselves could cause great morbidity and death if not corrected in the young. Thus, pediatric scientists devoted great attention to developing the biochemical tools to diagnose these conditions and introduced corrective measures through fluid and electrolyte replacement therapies. The important roles of iodine, vitamins, minerals, and amino acids were studied and recognized. Cretinism, rickets, and scurvy, so prevalent at the turn of the century, could now be treated and prevented. Important new findings in many medical fields laid the groundwork for many of the present day medical disciplines, such as hematology, oncology, hepatology, nephrology, pulmonology, cardiology, ophthalmology, and endocrinology. The purification and synthesis of steroid hormones, insulin, and GH have made it possible to treat or cure many endocrinopathies.


    National Institutes of Health (NIH)
 Top
 Introduction
 National Institutes of Health...
 General Clinical Research...
 Current Trends in Clinical...
 Conclusion
 References
 
By 1930 the general population was beginning to see the importance of scientific research in human disease, and Congress established the NIH. In 1942, the NIH moved to the Bethesda, Maryland, campus and was joined by the previously established National Cancer Institute in 1944. During the postwar years, public demand led to the development of Institutes dedicated to other disease categories and organ systems, each supporting research in the area of their interest from a single federal appropriation. The central coordination for peer review of applications was conducted through the newly established Research Grants Office. While research on disorders was conducted in all of the Institutes, most of the research related to childhood disorders was supported by the National Institute of Child Health and Human Development.

In 1953, eight NIH Institutes participated in the opening of the Clinical Center to support the clinical research for intramural investigators. In this building, inpatient wards were placed in close proximity to the investigators’ laboratories to facilitate what is often called "bench to bedside" medical or clinical research. The very active participation of young investigators serving their Public Health Service commitments led to a period rich in scientific discovery. By 1987 the Clinical Center had become the largest research hospital dedicated to clinical investigation. There were 495 inpatient beds.


    General Clinical Research Centers
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These physician-scientists who had participated and contributed notable discoveries in medical science while working in the Clinical Center of the NIH persuaded Congress in 1959 that the Nation should benefit from the discoveries of basic research as rapidly as they became available in academic institutions throughout the country. The Committee on Labor stated that "the time has come to consider creating, in part with Federal funds, a number of centralized facilities, either within a single university or among a group of universities to provide highly integrated research opportunities and services to large numbers of investigators and research groups" (3). In 1960, subsequently, Congress appropriated 3 million dollars for six NIH Institutes (Cancer, Mental Health, Heart, Arthritis and Metabolic Diseases, Allergy and Infectious Diseases, and Neurologic Diseases and Blindness) to support General Clinical Research Centers (GCRC) in academic medical centers throughout the country. The NIH definition of a GCRC was "a distinct organizational and physical entity providing a continuing framework for a clinical research effort, including the necessary laboratory, clinical and supporting services." The stated intent was that the GCRC were designated as loci for investigation, created to supplement, rather than supplant, ongoing medical research. They were to be established as discrete units or research wards apart from general medical care wards and were to contain 10–20 patient beds. They were to have stable, well-trained nursing and dietetic staffs, as well as specialized laboratory facilities.

The research to be conducted on the GCRC had to be multicategoric and multidepartmental in approach, and be supervised by an interdepartmental supervisory committee. Support for the research was to be derived from research and training grants, except for hospitalization and infrastructure costs. The program was very popular, and by 1969 the 95 centers outstripped the available appropriated funds (Fig. 1Go). Throughout the years, many significant discoveries were made in nutrition, metabolic and hormonal diseases, cancer, cardiovascular diseases, infectious diseases, and others. The earliest studies that led to transplantation of the kidney, liver, heart, and bone marrow were conducted on GCRC, as well as the early use of computerized tomography, positron emission tomography scans, and magnetic resonance imaging.



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Figure 1. Number of centers vs. years.

 
From inception to the present, GCRC function has reflected the national trends in medicine. Since clinical protocols first began to be conducted in outpatient settings in 1979, the number of outpatients visits has increased steadily, even as inpatient utilization has leveled off over the past 5 years (Fig. 2Go). At the same time, the studies have become more diverse rather than clustering around endocrine and metabolic disorders. Most notably, with the emergence of health maintenance organizations decreasing funds available for clinical research, the GCRC have become an oasis for clinical investigators within the academic institutions.



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Figure 2. Inpatient days vs. outpatient visits.

 
Currently, 77 GCRC are located in academic medical centers throughout the country, housing 8252 investigators whose 6145 protocols are supported by more than 1.3 billion dollars awarded by the United States Public Health Service. The total budget for fiscal year 1999 supporting the GCRC infrastructure was 204 million dollars.

Of these GCRC, 63 admit adults and children, 9 are exclusively dedicated to pediatric patients, and one is cofunded by the National Institute of Aging. Table 1Go lists the Pediatric Centers, GCRC with Pediatric satellites, and GCRC with Neonatal Intensive Care Units. From 1992–1998, the total amount of funds provided by the GCRC program has increased for support of pediatric research (Table 2Go). In fiscal year 1998, the most recent year for which data are complete, there were 1410 pediatric research protocols, 23% of the total GCRC activity. The major research areas addressed were rare diseases, acquired immunodeficiency syndrome, endocrinology, and diabetes. Studies in the neonatal age group revolved around evaluation of protein and growth factors in premature infants, the role of steroids and other hormones in prevention of bronchopulmonary dysplasia, and the evaluation of the hypothalamic-pituitary-adrenal axis following steroid withdrawal. Also of interest were protocols evaluating maternal nutrition or stress on the size and development of the newborn, as well as the late adolescent and young adult outcomes of babies with very low birth weights. Research in diabetes was vigorous with many GCRC participating in the Diabetes Prevention Trial, as well as protocols with other preventive strategies. Most of the work characterizing the phenotype/genotype correlations of maturity onset diabetes in the young has been accomplished by investigators using the GCRC. There are many studies attempting to correlate insulin resistance to obesity, coronary artery disease, and genetic biomarkers. Because hypoglycemia, especially nocturnal, is such a barrier to implementation of the stringent diabetes control required to prevent complications, many investigators are determining pathophysiologic and cognitive correlates of low blood sugars.


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Table 1. GCRC: pediatric, with pediatric satellites and with neonatal intensive care units

 

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Table 2. Infrastructure funding for pediatric research protocols

 
In the area of endocrinology, there are numerous studies that span the whole discipline from sophisticated phenotype/genotype correlations in congenital adrenal hyperplasias, myotonic dystrophy and congenital nephrogenic diabetes insipidus, to a variety of therapies for rare disorders, such as adrenoleukodystrophy, as well as those affecting growth and pubertal development.


    Current Trends in Clinical Research
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 Introduction
 National Institutes of Health...
 General Clinical Research...
 Current Trends in Clinical...
 Conclusion
 References
 
Today, we are poised before the second greatest milestone in medical science — the detailed characterization of the human genome that may shift the focus of medicine to genetic and environmental contributants. (4) The expanding enormity of this task demands an equally formidable infrastructure. To correlate the vast and previously unimaginable stores of knowledge, we now rely on technologically sophisticated devices using high-speed computers. This leads to new disciplines such as bioinformatics and functional imaging. It is reasonable to hope that as the sequence of the human genome becomes available, a more complete understanding of the basic mechanisms of life will allow Osler’s (1) ambitions to be realized. The knowledge of the molecular essence will dramatically accelerate the development of new strategies for the diagnosis, prevention, and treatment of disease. New information regarding the contribution of genetic differences to the development of the risk of contracting complex diseases and individualized responses to therapies will become available. Thus, it can be expected that once again the face of medical science and investigation will change. New understanding of the genetic contributions to human growth, development, aging, as well as disease, and the development of rational, individualized strategies for eliminating or minimizing disease phenotypes characterized by known pathophysiological structural and functional changes will evolve.

At the same time, startling new research suggests that adult diseases like diabetes, obesity, cardiovascular disease, stroke, and breast cancer, rather than determined by genetic predisposition or unhealthy living, may actually be rooted in the period of development before birth (5, 6). Samuel Taylor Coleridge (1772–1834) stated that "the history of man for the nine months preceding his birth would probably be more interesting and contain events of greater moment, than all the threescore and ten years that follow it." New scientific explorations provide compelling proof that the health that is enjoyed throughout life is determined to a large extent by the conditions during fetal development.

Crisis in clinical research

With so much excitement, so many opportunities, and so much promise for future discoveries, why is clinical research in a state of crisis? Why is the crisis even more pronounced when it concerns the opportunities open for children to benefit from clinical research?

Dr. James B. Wyngaarden (7) sounded the alarm in 1979, warning that the clinical researcher was becoming an "endangered species". His analysis of the NIH quantitative data on the clinical investigator pool from 1971–1978 led to the conclusion that "it is the progressive decline in the number of new entries that constitutes the danger to the survival of the species in the numbers and quality needed to maximize the rate of progress against the serious diseases of mankind." The progressive decline occurred despite the fact that the success rates of M.D. and Ph.D. applicants for NIH grants were equal. These findings were confirmed by others: Dr. Edward H. Ahrens, Jr., in his 1992 publication The Crisis in Clinical Research: Overcoming Institutional Obstacles, The Institute of Medicine Report (1994) entitled Careers in Clinical Research, Obstacles and Opportunities, as well as the National Institutes of Health Director’s Panel on Clinical Research. Clinical Research, Perceptions, Reality and Proposed Solutions," published in 1998 (8, 9, 10). Dr. Leon Rosenberg (11) has predicted that by the year 2003 there will no longer be physician scientists conducting clinical research. These dire predictions, based on intensive scrutiny of available data and trends, have led many organizations such as the American Medical Association (AMA) and the Association of American Medical Colleges (AAMC) to organize focus groups, retreats and a National Summit on Clinical Research to recommend new paradigms for training, career, and practice of clinical research and financial support to maintain the excellence of medical science and education within this country (12).

These efforts have led the NIH to enhance training and career development opportunities for scientists who have elected to devote their research efforts to patient-oriented research. A new K series of awards has been announced: K30 Institutional Curriculum Awards, K23 Mentored Patient-Oriented Research Career Development Awards, and K24 Midcareer Investigator Awards in Patient-Oriented Research; a number of these have been peer reviewed and awarded. Within the GCRC, the Clinical Associate Physician Award was expanded to include the higher salary, greater ancillary support, and longer duration of the K23. In addition to these extramural awards, there are a number of career development initiatives for medical student training, K22 intramural/extramural awards, and medical school loan forgiveness for trainees in the intramural community.

An additional concern is that the total number of young pediatricians choosing subspecialties within their discipline is declining (Fig. 3Go). Of the 583 pediatricians in the 3rd yr of subspecialty fellowships in 1999, 140 have chosen careers in neonatal-perinatal medicine. American medical graduates account for 57% of subspecialty fellows (13). The future of pediatric endocrinology seems dismal with only 27 fellows training throughout the country. Irrespective of the increase in support provided by the NIH awards, there simply will not be enough candidates to fill the ranks.



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Figure 3. Pediatric Subspecialty Tracking Information.

 
These statistics and the recommendations of many panels and reports have led to an evaluation of career tracks for physicians. To date, the programs designed to interest medical students in clinical research have accommodated only a few, select individuals per year. These have included the NIH, Howard Hughes and Four School Program. The National Center for Research Resources is proposing to broaden both the scope and level of support for medical students to participate in a full year of didactic and mentored clinical research at their local GCRC. The National Center for Research Resources is also planning to reinstate the Clinical Research Scholars program for those individuals who, prior to or during their fellowship, wish to take 1 or 2 yr of didactic course work that could lead either to an advanced degree in a topic related to clinical investigation or be combined with a K23 to broaden their clinical research career development program. Beyond these opportunities, the K24 award can provide up to 10 yr of support for mentors of clinical research. Thus, together the K23 and K24 awards could lead to 15 yr of NIH support to establish an individual in clinical research.

Inclusion of children in clinical research

The demands for pediatric research expertise in all disciplines, but especially endocrinology, are increasing. It was recognized in the early 1990s, when rules requiring the inclusion of women and minorities in clinical trials became law, that children were often excluded from trials because of the perception of increased risk. The American Academy of Pediatrics (AAP) and the NIH concluded that 10% of all NIH-funded research projects inappropriately excluded children from participating as research subjects. As a result, in 1998 the NIH issued a new policy that requires that for all patient-oriented, clinical research protocols the investigators need to justify the exclusion of children (defined as neonates to age 21) or otherwise make appropriate arrangements for inclusion. Children should be studied in environments appropriate for children, by physicians qualified to treat children, and in sufficient numbers to be able to derive conclusions from their participation (14). The Food and Drug Administration, likewise, requires manufacturers to submit data on the safety and effectiveness of drugs that are intended for use in children. There has been insufficient additional Federal funding to adequately expand the existing programs. The National Institute of Child Health and Human Development (NICHD) funds Pediatric Pharmacology Research Units in academic medical centers to assist pharmaceutical companies in conducting drug studies in children. However, the NICHD budget does not allow many large-scale clinical trials in children.

Another major problem for children, as well as the aged and infirm, is drug formulation. Large dose pills or capsules do not lend themselves to delivery of smaller doses in accurate and palatable ways. In addition to drug studies, devices need to be miniaturized, adapted, and tested for use in children. All of the above are technical problems, requiring applications of currently available knowledge and methods to implement. Yet, children have no voice in politics, often lack insurance, and, thus, are in danger not only of not receiving modern up-to-date care but also being denied the benefits of the newest, most effective treatments.

Future opportunities in clinical research

As we look toward the next century, there are many predictions. What will the lives of children be like? What will the future hold for medical science? We can predict with certainty that the rapid, phenomenal advances in science will change our lives and medicine in remarkable ways. We are already planning the uses of pharmacogenetics and pharmacogenomics with the potential for providing an individualized genetic blueprint based on which we will be able to calculate risks for developing certain conditions and determine the most effective preventive measures. It will be possible to customize medication doses based on gene-based diagnostics. It is expected that gene therapy will prevent and cure diseases. The discovery of gene function will lead to a better understanding of basic biological defects and rational drug design. Environmental influences on fetal development, gene activation or deactivation, and gene expression will be known, and positive steps will be taken to prevent health problems. Technological advances in diagnostic capabilities such as spiral computerized tomography, high magnetic resonance imaging, electrolyte and glucose sensors coupled to computerized delivery systems, stem cell therapies, and potential organ fortification or replacement are all on the horizon. Efforts will intensify to understand brain function, memory, and mental disorders. New ways of producing vaccines will provide economical and effective ways of eradicating illnesses ranging from the common cold to pandemic influenza. For heart disease there will be better noninvasive diagnostic tests, better surveillance methodologies, and therapies not only with drugs but genes and hormones. Similarly, there will be the possibility to target specific malignant cells through antibody tags or angiogenesis factors. New antibiotics will overcome drug resistance for infections, and new drugs with genetic targeting will not only alleviate symptoms but treat root causes of diseases such as Alzheimer’s or multiple sclerosis. As the population lives longer, there will be more emphasis on spirituality, relaxation, exercise, and low calorie diets with vitamin, antioxidant, and protein supplements. We hope for a gentler, kinder world with less stress and violence, especially for the children.


    Conclusion
 Top
 Introduction
 National Institutes of Health...
 General Clinical Research...
 Current Trends in Clinical...
 Conclusion
 References
 
Scientific discovery is advancing with almost miraculous strides. Vast amounts of knowledge are accumulating not only from the medical sciences but other disciplines, such as biotechnology, engineering, physics, and others. The challenge is to discern which discoveries hold the potential for human application and then rapidly and effectively implement them. This work can best be done by clinicians knowledgeable about medicine, patient care, and underlying scientific principles. To meet these challenges, unprecedented opportunities have evolved. The NIH budget has increased substantially. A new Clinical Research Center is under construction on the NIH campus. The GCRC are poised to expand their activities into previously understudied areas and participate in the new developments in bioinformatics and technologically sophisticated instrumentation. Extensive career development programs for those interested in clinical research are in place. These can accommodate individuals ranging from medical students to those more senior who wish to make a mid-career change and devote their efforts to patient-oriented research. This is a time of great excitement in science. Those with a spirit of inquiry and dedication to discovery with its potential to improve the health of humankind are sure to be rewarded.


    Footnotes
 
1 The ideas and opinions expressed in this manuscript are those of the author and do not represent any position or policy of the NIH or any other federal agency. Back

Received October 14, 1999.

Accepted October 14, 1999.


    References
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 Introduction
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 Current Trends in Clinical...
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  1. Osler W. 1902 Chauvinism in medicine. Montr Med J. 31:684–699.
  2. Research and Discovery in Medicine. 1976 Contributions from Johns Hopkins. Baltimore and London: The Johns Hopkins University Press.
  3. HEW Appropriations Report 425, 1959.
  4. Collins FS. 1999 Shattuck Lecture: medical, and societal consequences of the Human Genome Project. N Engl J Med. 28–37.
  5. International Conference on Fetal Origins of Adult DiseaseNational Institutes of Health, Bethesda, MD, 1999.
  6. Shaped by life in the womb. Science and technology.Newsweek. Sept. 27:1999.
  7. Wyngaarden JB. 1979 The clinical investigator as an endangered species. N Engl J Med. 301:1254–1259.[Medline]
  8. Ahrens Jr EH. 1992 The crisis in clinical research. Overcoming institutional obstacles. Oxford: Oxford University Press, Inc.
  9. Institute of Medicine. 1994 Careers in clinical research. Obstacles and opportunities. National Academy Press.
  10. Nathan DG. 1998 The National Institutes of Health Director’s Panel on Clinical Research. Clinical research: perceptions, reality, and proposed solutions. J Am Med Assoc. 280:1427–1431.[Abstract/Free Full Text]
  11. Rosenberg LE. 1999 The physician-scientist: an essential and fragile link in the medical research chain. J Clin Invest. 103(12):1621–1626.
  12. Thompson JN. 1997 Preventing the extinction of the clinical research ecosystem. J Am Med Assoc. 278:241–245.[CrossRef][Medline]
  13. Tunressen WW. 1999 Workforce: results of 1998–1999 tracking. Pediatric Diplomates 5–7.
  14. National Institutes of Health. 1998 NIH guide on inclusion of children in research. NIH Guide 1999; (March 6).




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