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
|
---|
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)
|
---|
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
|
---|
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 1020 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. 1
). 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.
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. 2
). 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.
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 1
lists the
Pediatric Centers, GCRC with Pediatric satellites, and GCRC with
Neonatal Intensive Care Units. From 19921998, the total amount of
funds provided by the GCRC program has increased for support of
pediatric research (Table 2
). 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.
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
|
---|
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 Oslers (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 (17721834) 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 19711978 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
Directors 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. 3
). 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.
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
Alzheimers 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
|
---|
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. 
Received October 14, 1999.
Accepted October 14, 1999.
 |
References
|
---|
-
Osler W. 1902 Chauvinism in medicine. Montr
Med J. 31:684699.
-
Research and Discovery in Medicine. 1976 Contributions from Johns Hopkins. Baltimore and London: The Johns
Hopkins University Press.
-
HEW Appropriations Report 425, 1959.
-
Collins FS. 1999 Shattuck Lecture: medical, and
societal consequences of the Human Genome Project. N Engl J
Med. 2837.
-
International Conference on Fetal Origins of Adult
DiseaseNational Institutes of Health, Bethesda, MD, 1999.
-
Shaped by life in the womb. Science and technology.Newsweek. Sept. 27:1999.
-
Wyngaarden JB. 1979 The clinical investigator as
an endangered species. N Engl J Med. 301:12541259.[Medline]
-
Ahrens Jr EH. 1992 The crisis in clinical
research. Overcoming institutional obstacles. Oxford: Oxford
University Press, Inc.
-
Institute of Medicine. 1994 Careers in clinical
research. Obstacles and opportunities. National Academy
Press.
-
Nathan DG. 1998 The National Institutes of Health
Directors Panel on Clinical Research. Clinical research: perceptions,
reality, and proposed solutions. J Am Med Assoc. 280:14271431.[Abstract/Free Full Text]
-
Rosenberg LE. 1999 The physician-scientist: an
essential and fragile link in the medical research chain. J Clin
Invest. 103(12):16211626.
-
Thompson JN. 1997 Preventing the extinction of the
clinical research ecosystem. J Am Med Assoc. 278:241245.[CrossRef][Medline]
-
Tunressen WW. 1999 Workforce: results of 19981999
tracking. Pediatric Diplomates 57.
-
National Institutes of Health. 1998 NIH
guide on inclusion of children in research. NIH Guide 1999; (March
6).