Chronic Fatigue Syndrome: CDC and NIH Research Activities Are Diverse,
but Agency Coordination Is Limited (Letter Report, 06/02/2000,
GAO/HEHS-00-98).
Pursuant to a congressional request, GAO provided information on the
chronic fatigue syndrome (CFS) research activities administered by the
Centers for Disease Control and Prevention (CDC) and the National
Institutes of Health (NIH), focusing on: (1) the CFS activities that CDC
and NIH have supported; (2) the funds and resources CDC and NIH have
devoted to CFS research; and (3) how CDC and NIH coordinate research and
involve patient organizations and external researchers in developing
their CFS research programs.
GAO noted that: (1) for approximately the last 12 years, both CDC and
NIH have conducted a broad range of activities related to CFS; (2) CDC
has focused largely on prevalence and disease causes, including the
search for infectious and immunological abnormalities; (3) NIH has
focused primarily on CFS' effects on bodily systems and possible causal
agents; (4) both agencies' work has generally been consistent with their
missions, and both have initiated most of the projects that have been
requested in appropriations report language and the projects defined in
their program plans; (5) funds for CFS research have increased at both
CDC and NIH since 1987; (6) much of the increase occurred in the first
few years; (7) over the past 4 years, funds have generally not
increased; (8) at CDC, the lengthy and uncertain process for allocating
CFS funds to the branch responsible for most of the CFS work has
resulted in delays in undertaking particular projects; (9) further,
CDC's redirection of funds has resulted in reductions in CFS resources
that have impeded the agency's CFS research; (10) however, CDC has begun
a process to restore all redirected CFS funds; (11) NIH has taken a
number of steps to facilitate the funding of CFS projects, including
issuing program announcements, establishing a special emphasis panel to
review CFS grant applications, and using a discretionary program to fund
additional studies; (12) NIH has also supported a number of research
centers on CFS; (13) coordination between CDC and NIH and their use of
input from external researchers and patient advocates in developing
agency research programs have been limited; (14) CDC and NIH have not
jointly conducted research, although CDC's advisory panel and external
peer reviewers have recommended that CDC undertake such a collaboration;
(15) CFS coordinating committee (CFSCC), chartered to encourage federal
coordination, has helped to facilitate some interagency communication,
but it has not provided an effective forum for developing coordinated
research programs; and (16) certain shortcomings in how CFSCC conducts
its work may have limited its usefulness, although the committee has
made recent efforts to improve its effectiveness.
--------------------------- Indexing Terms -----------------------------
REPORTNUM: HEHS-00-98
TITLE: Chronic Fatigue Syndrome: CDC and NIH Research Activities
Are Diverse, but Agency Coordination Is Limited
DATE: 06/02/2000
SUBJECT: Medical research
Health research programs
Diseases
Interagency relations
Funds management
Research grants
IDENTIFIER: NIH Extramural Research Program
NIH Intramural Research Program
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GAO/HEHS-00-98
Appendix I: Background on Chronic Fatigue Syndrome
30
Appendix II: Accounting Issues at CDC
34
Appendix III: CDC Research Efforts and Publications
37
Appendix IV: NIH Research Efforts and Grants
44
Appendix V: Congressionally Requested CFS Activities for CDC
and NIH
54
Appendix VI: External Review Recommendations to CDC and NIH
59
Appendix VII: NIH Expenditures on CFS Research, by Institute and
Center
64
Appendix VIII: NIH Activities in Support of CFS Research
65
Appendix IX: Comments From the Department of Health and
Human Services
69
Table 1: U.S. Studies of CFS Prevalence Based on Clinical
Evaluation of Samples of Local Populations 32
Table 2: NIH Disposition of Projects Identified by CRISP From 1997 Through
1999 Not Included in NIH's List 47
Table 3: NIH-Funded R01 (Research Project) Grants Related to CFS 48
Table 4: NIH-Funded Intramural Research Projects Related to CFS 49
Table 5: NIH-Funded Grants and Projects Not Including R01
(Research Project) Grants and Intramural Projects Related
to CFS 50
Table 6: NIAID Cooperative Research Center Projects Related to
CFS 52
Table 7: Congressionally Requested CFS Activities for CDC 54
Table 8: Congressionally Requested CFS Activities for NIH 57
Table 9: Recommendations From CDC's 1996 Peer Review and
Agency Response 59
Table 10: Recommendations From CDC's 1999 Peer Review, Board of Scientific
Counselor Review, and Meeting With Patient
Advocates, and Agency Response 61
Figure 1: CDC Funding, Fiscal Years 1988 Through 1999 14
Figure 2: NIH Expenditures, Fiscal Years 1988 Through 1999 16
Figure 3: Proportion of CFS Funds Retained at Each Level of
CDC, Fiscal Years 1998 Through 1999 19
Figure 4: CDC Publications 39
CDC Centers for Disease Control and Prevention
CFS chronic fatigue syndrome
CFSCC CFS Coordinating Committee
CRISP Computer Retrieval of Information on Scientific Projects
FDA Food and Drug Administration
HHS Department of Health and Human Services
NCI National Cancer Institute
NCRR National Center for Research Resources
NHLBI National Heart, Lung, and Blood Institute
NIAID National Institute of Allergy and Infectious Diseases
NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases
NICHD National Institute of Child Health and Human Development
NIH National Institutes of Health
NIMH National Institute of Mental Health
NINDS National Institute of Neurological Disorders and Stroke
Health, Education, and
Human Services
B-283171
June 2, 2000
The Honorable Harry Reid
United States Senate
Dear Senator Reid:
Chronic fatigue syndrome (CFS) is a debilitating and complex disorder that
potentially affects more than 800,000 Americans--yet it has no known cause
or cure. CFS is defined by profound fatigue that is not improved by bed rest
and other symptoms, such as weakness, muscle pain, cognitive difficulties,
and problems with sleep. CFS is diagnosed only by excluding other possible
causes of the fatigue and only after the fatigue has persisted for at least
6 months.
Since fiscal year 1988, congressional appropriations committee reports have
asked the Centers for Disease Control and Prevention (CDC) and the National
Institutes of Health (NIH) to initiate investigations and projects related
to CFS, a disorder each agency began investigating in the mid-1980s. The
goals of their work have included defining CFS and determining its
prevalence and cause or causes. CDC and NIH research to date has focused
largely on estimating prevalence, investigating suspected clusters of CFS,
and examining possible causes. In 1996, the Secretary of the Department of
Health and Human Services (HHS) established a committee of representatives
from CDC, NIH, and other federal agencies; scientists; and patient advocates
largely for the purpose of coordinating federal research efforts on CFS.
Since fiscal year 1987, NIH has devoted approximately $57.6 million to the
study of CFS through intramural and extramural CFS grants. The committee
reports indicated a level of funding to support CFS work at CDC
totaling $44.7 million through fiscal year 1998.1 For fiscal years 1995
through 1998, the committees recommended that CDC spend $23.4 million on the
study of CFS. However, in 1999, the Inspector General of HHS reported that
CDC had expended $8.8 million on activities unrelated to CFS and $4.1
million on inadequately documented indirect costs--as much as half of the
funds the committees recommended for CFS. Because of concerns related to the
redirection of CFS funds at CDC and questions raised by patient advocates
about the lack of research progress, you asked us to (1) identify the CFS
research activities that CDC and NIH have supported, (2) determine the funds
and resources CDC and NIH have devoted to CFS research, and (3) describe how
CDC and NIH coordinate research and involve patient organizations and
external researchers in developing their CFS research programs.
For this study, we reviewed documents from CDC and NIH and talked with
agency officials; reviewed minutes of and attended meetings of HHS' CFS
Coordinating Committee (CFSCC); and talked with current and past federal,
patient advocate, and scientific members of the chartered committee. We
reviewed work in the years that each agency devoted funding to CFS research:
for CDC, fiscal years 1988 through 1999; for NIH, fiscal years 1987 through
1999. We did not evaluate the quality of the research conducted. We
conducted our work between July 1999 and May 2000 in accordance with
generally accepted government auditing standards.
For approximately the last 12 years, both CDC and NIH have conducted a broad
range of activities related to CFS. CDC has focused largely on prevalence
and disease causes, including the search for infectious and immunological
abnormalities. NIH has focused primarily on CFS' effects on bodily systems
and possible causal agents. Both agencies' work has generally been
consistent with their missions, and both have initiated most of the projects
that have been requested in appropriations report language and the projects
defined in their program plans.
Funds for CFS research have increased at both CDC and NIH since 1987. Much
of the increase occurred in the first few years; over the past 4 years,
funds have generally not increased. At CDC, the lengthy and uncertain
process for allocating CFS funds to the branch responsible for most of the
CFS work has resulted in delays in undertaking particular projects. Further,
CDC's redirection of funds has resulted in reductions in CFS resources that
have impeded the agency's CFS research. However, CDC has begun a process to
restore all redirected CFS funds. NIH has taken a number of steps to
facilitate the funding of CFS projects, including issuing program
announcements, establishing a special emphasis panel to review CFS grant
applications, and using a discretionary program to fund additional studies.
NIH has also supported a number of research centers on CFS.
Coordination between CDC and NIH and their use of input from external
researchers and patient advocates in developing agency research programs
have been limited. CDC and NIH have not jointly conducted research, although
CDC's advisory panel and external peer reviewers have recommended that CDC
undertake such a collaboration. CFSCC, chartered to encourage federal
coordination, has helped to facilitate some interagency communication, but
it has not provided an effective forum for developing coordinated research
programs. Certain shortcomings in how CFSCC conducts its work may have
limited its usefulness, although the committee has made recent efforts to
improve its effectiveness.
HHS commented on a draft of this report and generally agreed with our
findings, particularly that CFSCC could be more effective.
Because there is currently no known biological way to differentiate cases of
CFS from other conditions, researchers use clinical descriptions of symptoms
to define CFS. To date, CFS has had two different case definitions. The
first case definition, developed in 1988, required that, in addition to
fatigue, patients had to meet 8 of 14 symptom or physical criteria. In 1994,
the definition was revised to include only four of eight symptoms in
addition to fatigue. An additional revision of the case definition is being
considered. In addition, other terms have been used to describe the
illness--such as chronic fatigue and immune dysfunction syndrome and myalgic
encephalomyelitis--and other definitions of CFS are used in other countries.
Estimates of CFS prevalence in the United States have varied from 2.0 to 7.3
per 100,000 under the first definition to 238 to 422 per 100,000 under the
revised case definition. This last estimate translates to about 836,000
Americans. (For a more detailed discussion of CFS case definition,
prevalence estimates, and research on possible causes, see app. I.)
Evidence to support many of the hypothesized causes of CFS has been
insufficient, but other hypotheses continue to be developed. And while CFS
has no known cause or cure, there are some therapies for CFS that are
directed at relieving patient symptoms.2
CDC's CFS work is performed largely in the Viral Exanthems and Herpesvirus
Branch within the Division of Viral and Rickettsial Diseases under the
National Center for Infectious Diseases. CFS work is assigned to this branch
because early hypotheses about the causes of CFS included viruses covered by
the branch, such as Epstein-Barr virus and herpes viruses. CDC allocates
funds budgeted for CFS to the branch through the center and the division.
Annually, each branch of the Division of Viral and Rickettsial Diseases
presents a review of its program activities, plans, and accomplishments.
Most of CDC's CFS research is conducted extramurally, primarily through
research contracts. Intramural work is planned by individual branch chiefs
and reported in these reviews as part of the branches' plans. In 1998, it
was alleged that in fiscal years 1995 through 1998, CDC had spent funds that
had been budgeted for CFS on other programs and had misled the Congress
about how it had spent these funds. At CDC's request, HHS' Inspector General
conducted an audit of the CFS program for these years and found that about
one-third of the funds ($8.8 million) had been spent on non-CFS-related
activities. An additional one-fifth ($4.1 million) of funds were indirect
costs not adequately documented to determine applicability to CFS. While the
Inspector General noted that CDC was not legally prohibited from spending
funds this way, the Inspector General found that these discrepancies
resulted from deficiencies in CDC's internal control system for handling
direct and indirect costs. (See app. II.)
NIH's CFS research is conducted by both intramural scientists employed by
NIH as well as extramural scientists who are awarded grants or contracts for
their work. The largest portion of NIH's CFS work has been performed within
the National Institute of Allergy and Infectious Diseases (NIAID). Other NIH
institutes and centers that have funded CFS research include the National
Institute of Mental Health; the National Institute of Neurological Disorders
and Stroke; the National Center for Research Resources; the National Cancer
Institute; the National Heart, Lung, and Blood Institute; the National
Institute of Arthritis and Musculoskeletal and Skin Diseases; and the
National Institute on Child Health and Human Development. Four additional
NIH institutes and centers have joined the solicitation for grant
applications for work on CFS; but, to date, none have been funded by these
units.3 External grant applications are reviewed by special emphasis panels
of external scientists who rate the merit of each application. Final
decisions about the merit of grants are subsequently made by the relevant
institute's external advisory council, which meets three times each year.
Every 4 years, each laboratory in the intramural research program is
reviewed by its institute's board of scientific counselors. Recently, NIH
moved the responsibility for coordinating efforts on CFS from NIAID to the
Office of the NIH Director. NIH officials told us this was to centralize
these efforts at NIH.
To help ensure coordination of federal research efforts related to CFS, HHS'
Assistant Secretary for Health in 1990 assembled a group of federal
researchers--adding nonfederal scientists and patient advocates as
consultants in 1994--to form an interagency committee. Then in 1996, the
Secretary of HHS chartered CFSCC, in part, to ensure coordination and
communication regarding CFS. The committee consists of seven members,
appointed by the Secretary, and five ex-officio members. Of the seven
appointed members, three are biomedical research scientists; two have
expertise in health care services or disability issues or represent private
health care services insurers; and two represent voluntary organizations
that serve people with CFS. Members are invited to serve for overlapping
4-year terms. The ex-officio members are representatives from CDC, NIH, the
Food and Drug Administration (FDA), the Health Resources and Services
Administration, and the Social Security Administration.4 The Assistant
Secretary for Health chairs the committee. CFSCC management and support
services are provided on a 2-year rotating basis between NIH and CDC, and
the ex-officio representative from that agency serves as cochair. Meetings
are held approximately two times a year and are open to the public.
CFSCC membership is different from that of all other HHS advisory
committees. For nearly all of HHS' 12 other similar advisory committees, the
federal members serve in an ex-officio capacity and are nonvoting. CFSCC is
the only committee chaired by federal representatives when there are
nonfederal members of the committee. All other committees with nonfederal
members have a nonfederal member as the chair of the committee.
While researchers and advocates have expressed concerns about the breadth of
CFS research at CDC and NIH, we found the agencies have conducted a broad
range of activities related to CFS. The agencies have also undertaken
efforts to educate patients and physicians. These activities and efforts
have generally been consistent with what would be expected based on the
agencies' mission statements. Further, both agencies initiated the majority
of studies and activities that were requested in appropriations committee
reports. Finally, the agencies generally conducted activities mentioned in
their own program plans and responded to recommendations of external expert
reviewers.
Their Missions
CDC has conducted activities in most areas of its recent mission statements
for its CFS program. For example, CDC has led efforts to develop a rigorous
case definition for CFS, which is necessary to evaluate whether CFS is a
single disease or a set of symptoms that could have multiple causes. The
agency has also conducted a number of surveillance studies to determine the
prevalence of CFS, starting with a study using physician referrals to
identify possible CFS patients and later shifting to a more active
community-based approach. In addition, CDC has examined a number of possible
CFS risk factors, including viral and immunological ones, and has relied on
data collected from its surveillance studies to describe the natural history
of CFS. To date, however, the agency has not identified any cause or causes
for CFS.
As part of its CFS mission, CDC has also undertaken a variety of efforts to
educate practitioners, professionals, and the public, including scientific
publications, a web site, a toll-free hot line, and a booklet about CFS.
Because there have been so few objective findings to date, it has not been
possible for CDC to develop control strategies. (See app. III for more
details on CDC's research efforts and a list of its CFS-related
publications.)
With CDC's direction of an additional $12.9 million to its CFS program over
4 years--to compensate for redirected funds in prior years--work has been
planned in a number of additional areas, including a national survey to
estimate prevalence, a national patient registry, a workshop to determine if
the current case definition for CFS should be revised, endocrine and sleep
studies, and genetic tests of tissue samples. For example, in May 2000, CDC
held a 3-day workshop to assess current clinical and empirical knowledge
concerning the definition of CFS. Participants agreed that it was premature
to revise the case definition and that future revisions should be based on
data-driven research rather than consensus clinical opinion.
While CDC has conducted research in a broad range of areas, the agency has
been criticized by researchers and patient advocates about the lack of
openness of its efforts. For example, because CDC sometimes does not release
findings from its studies until they are published in a professional
journal, the latest information may not always be immediately available.
However, this is a common practice among scientific researchers, and
obtaining peer review prior to publication is used to ensure the integrity
of the communication. Further, CDC officials reported that the agency
follows its normal procedures in releasing results of its CFS studies. We
also found that CDC has periodically presented preliminary results from its
surveillance studies at scientific conferences and regularly reviews the
current status of its research at CFSCC meetings.
Within NIH, NIAID's intramural and extramural research programs have been
responsible for most of NIH's work on CFS, and the institute has supported
work on causes, prevalence, origin and development of diseases, diagnosis,
and treatment. NIH has funded investigations of a number of possible causes,
including immunologic, neuropsychologic, neuroendocrinologic, brain wave,
and infectious aspects of CFS. However, NIH, like CDC, has not yet been able
to identify a single cause or group of causes for CFS. NIAID has supported a
number of attempts to estimate the prevalence of CFS, particularly a large
epidemiological project in Chicago to study the socioeconomic and ethnic
variability of CFS. Early work to identify the origin and development of the
disease focused on the possible role of the Epstein-Barr virus and of immune
system deficiencies. Recent efforts involve postinfectious fatigue and blood
pressure irregularities in CFS patients. Some agency efforts to develop
diagnostic methods focus on the intensity of the symptoms and new
measurement tools to evaluate CFS patients. NIH has also supported several
projects with possible application to treatment, including modulating brain
chemistry, developing individually tailored exercise programs, trials of
pharmacologic agents, and studies of nonpharmacologic treatments. Given the
limited understanding of the causes of CFS, work on NIAID's goal of
furthering prevention has not been undertaken. Additional details about
NIH's CFS research efforts and lists of the grants and projects funded by
NIH are in appendix IV.
Some patient advocates have voiced concern that NIH has not funded specific
kinds of CFS research, such as research on mycoplasma and its possible
connection to CFS. However, we found no evidence that a grant proposal on
mycoplasma had ever been submitted. Patient advocates have also criticized
the types of CFS research that NIH has funded--in particular, psychiatric
research. Some believe that NIH has disproportionately funded research of
this type, but we found no such evidence. The National Institute for Mental
Health's funding reported for CFS is artificially high because it includes
funds for a large grant, of which only a small portion was related to CFS.
Congressional interest in CFS research was first expressed in fiscal year
1988.5 Since then, congressional report language, directed at both CDC and
NIH, has indicated areas of research that the appropriations committees
thought should be pursued. Both CDC and NIH have undertaken efforts in
nearly all these areas. (A list of requested activities and their status is
in app. V.)
Appropriations committees have requested in reports 33 distinct activities
for CDC, including development and implementation of a surveillance network,
continued tests related to specific suspected causes, and public information
and training initiatives. CDC has initiated work on most of these. For the
four areas where CDC did not initiate work, the agency reported that the
work was inappropriate or not feasible for them to pursue.
NIH has also been largely responsive to congressional committee direction,
appointing a CFS coordinator, ensuring appropriate representation to
advisory committees and boards, and encouraging studies of risk factors and
immunology. In report language, the appropriations committees have requested
NIH work in 34 areas. All but five activities have been pursued; NIH
considers some of those that have not been pursued infeasible.
Own Program Plans and Responded to Recommendations of External Reviewers
CDC and NIH produced annual reports outlining their activities and plans for
future work on CFS. For the most part, both agencies completed the work in
those plans. To help the agencies stay focused on their goals, the agencies'
review boards periodically examined the CFS program. At CDC, the CFS program
has undergone a number of reviews. In 1991, CDC conducted an internal peer
review of the CFS program by scientists from other CDC areas and programs.
In 1993, there was an external peer review of the Viral Exanthems and
Herpesvirus Branch, which included the CFS program. The CFS program
underwent peer reviews in 1996 and 1999 as well as a review by CDC's Board
of Scientific Counselors in 1999. At NIH, the National Advisory Allergy and
Infectious Diseases Council discussed the CFS program in 1995, although
components of the program were discussed at other meetings as well.
Scientists involved in the 1991 internal CDC peer review expressed concerns
in four areas: (1) the limited sample size proposed for a case control study
of CFS risk factors, (2) the statistical power of the case control study to
detect real differences, (3) the lack of representativeness of the sample of
patients referred by physicians in the surveillance study designed to
estimate prevalence, and (4) the extensiveness of the factors to be
evaluated in an exploratory study. The 1993 branch review suggested two
specific additions to CDC's study of possible causes of CFS. They also
recommended that CDC scientists contact those at NIH where a relevant study
was under way. Agency officials reported that there was no official agency
response to either review.
CDC's 1996 peer review, conducted by four scientists and two patient
advocates, made 18 recommendations; for the most part, CDC has undertaken
activities in response to these recommendations. CDC received a consistent
message from both the 1999 peer review and the review of its Board of
Scientific Counselors that they should look for more opportunities to
collaborate with other researchers, including possibly those at NIH. There
were a number of other recommendations from these recent reviews, and CDC
officials have reported many activities planned to address these
recommendations. (See app. VI.)
NIAID's National Advisory Allergy and Infectious Diseases Council has also
occasionally made recommendations about CFS research efforts. The council
has advocated that the agency support specific studies suggested by findings
from case demographics, encouraged continuing and expanding the CFS
Cooperative Research Centers program, and determined at a fall 1995 CFS
program review that NIAID should retain overall leadership of NIH's CFS
efforts but that a multidisciplinary research approach involving other
institutes should also continue, where appropriate. A subcommittee of the
council also recommended the agency develop work in a number of areas. NIH
has conducted investigations in all but two of these areas (studies of
patients with shorter duration of illness and issues related to pregnancy).
(See app. VI.)
NIH's
Researchers and patient advocates have expressed concerns about CDC's and
NIH's resources (funding and staffing) and funding mechanisms for CFS
research, and their potential effects on the agencies' ability to plan and
carry out research. Although CDC and NIH funds have increased over time,
stabilizing in recent years, their funding data may not fully reflect their
CFS expenditures due to each agency's process for tracking CFS funds.
Staffing directly related to CFS has increased in recent years at CDC, but
it has declined at NIH. We found that the processes and timing for
distributing funds within CDC impeded CFS research and may reflect
inadequate control on the part of the agency. Conversely, NIH has used a
number of mechanisms to facilitate the support of CFS research, including
program announcements, the formation of a special review panel for CFS grant
applications, and support of research centers.
Levels Have Been Flat Over the Past 4 Years
Since 1988, the congressional committee reports accompanying CDC's annual
appropriation act have expressed an expectation that specific funds would be
used for CFS research and other CFS projects. Although CDC has generally
requested each year the same level of funding for CFS as was received the
prior year, the committee reports suggest increasingly larger sums. The
amount of funds suggested in these reports has increased from $407,000 in
fiscal year 1988 to $6,497,000 in fiscal year 1999.6 (See fig. 1.) However,
since fiscal year 1995, the level of suggested funding increased only a
total of $455,000. Moreover, the HHS Inspector General review found that
over one-third of the funds ($8.8 million) in fiscal years 1995 through 1998
was spent on activities unrelated to CFS and another $4.1 million in
indirect costs was not adequately documented to determine applicability to
CFS . Regardless, CDC officials reported only one study--a survey of
adolescents--that it did not initiate because of insufficient funds, and the
agency has since determined that this study was not feasible for
methodological reasons.
CDC indicated that it has increased the number of staff working on CFS.7
Prior to 1996, permanent staff working on CFS filled approximately 5 to 8
positions; since then, the number of positions has increased to 13 to 15.
During these same periods, the staff has also changed from mostly permanent
employees to mostly temporary employees. The temporary staff have typically
been predoctoral or postdoctoral students or laboratory technicians.
NIH expenditures for both intramural and extramural CFS projects increased
from $782,000 in fiscal year 1987 to $6,892,000 in fiscal year 1999,8
although these expenditures declined slightly over the last 4 years. (See
fig. 2.) Further, while NIAID was the only institute to fund CFS research in
the first 2 years (fiscal years 1987 through 1988), with minimal support
from one other institute during the next 2 years, six institutes funded CFS
research in fiscal year 1999. (See app. VII.) It is important to note that
these figures may not accurately reflect expenditures for CFS. For the
National Institute of Mental Health, expenditures are likely overestimated
because projects are included even when only a small portion is relevant to
CFS. For other institutes, expenditures may be underestimated for at least
two reasons. First, if the institute or center has $250,000 or less in total
funding for a disease, it is not required to report spending for that
disease. Second, projects that are peripherally related to CFS may not have
been included in NIH's funding figures.
While NIH expenditures for CFS research have remained fairly stable over
recent years, staffing levels at NIAID, the only institute for which we have
data, have decreased.9 Between 1988 and 1996, the number of
full-time-equivalent intramural staff increased from 2.5 to 3.25 staff.
Since 1997, however, the number of intramural full-time-equivalent staff at
NIAID working on CFS decreased from 2 in 1997 to less than 1 in 1999. Most
of the intramural staff working on CFS in NIAID specialized in either
nursing or internal medicine. In addition to the intramural staff, NIAID has
a program officer assigned to the Virology Branch (which is responsible for
the extramural CFS work at NIAID). Over the years, the amount of time
devoted by the program officer to CFS work versus other work has ranged from
20 to 60 percent.10
Research
Concerns have been raised by patient advocates that funding practices at CDC
may create barriers to planning and carrying out CFS research. Specific
issues raised are that indirect costs charged to the CFS program are
inordinately high and that the distribution of CFS funds is not timely. We
found that, from fiscal years 1988 through 1999, an average of 45 percent of
CFS funds at CDC covered indirect costs, with funds being taken from
budgeted allocations at the agency (20 percent), center (13 percent), and
division levels (12 percent) prior to being distributed to the Viral
Exanthems and Herpesvirus Branch.11 (See fig. 3.) These set percentages were
taken from budgeted allocations without consideration for variability in use
of services across different programs. CDC officials told us that the agency
recently changed the way it calculates indirect costs at the agency level
and that these changes were made in a manner consistent with recommendations
in the Inspector General audit. In recent years (1998 through 1999),
therefore, total indirect costs have been closer to 37.5 percent. Changes in
methods for calculating indirect costs have not been implemented at the
center level or below.12 Regardless, CDC officials told us that other
programs within the Division of Viral and Rickettsial Diseases had similar
proportions of funds deducted for indirect costs, so these percentages are
not unique to CFS funds.
The HHS Inspector General review of CFS found that the distribution of
indirect costs agencywide may have been arbitrary and inconsistent, with
some programs being significantly overcharged while other programs were
charged far less than their fair share. The Inspector General also concluded
that the various centers and divisions within CDC were able to arbitrarily
determine the indirect costs for some or all of their programs, with no
assurance that those charges would be reasonable and consistent. Further,
the Inspector General found that the CFS program's indirect costs were
largely undocumented and generally excessive in relation to those of other
programs.
Although improvements in fund allocation have been made since 1998, the
allocations of funds at CDC have typically been received late in the fiscal
year--on average, more than 9 months into the fiscal year--which can
adversely affect the ability to plan research programs. Moreover, funding
allocations for the Viral Exanthems and Herpesvirus Branch have frequently
not included explicit funding amounts for CFS. The National Center for
Infectious Diseases has generally not received its final allocation from CDC
until mid to late spring for the fiscal year that began the prior October.13
The center then typically provided an allocation to the Division of Viral
and Rickettsial Diseases 1 month later and the Division provided final
allocation memorandums to the branches approximately 1 to 2 months after
that. These timelines are typical across CDC. In fiscal years 1997 and 1998,
the Viral Exanthems and Herpesvirus Branch received its allocation on July 7
or later--more than 9 months into the fiscal year.14 Traditionally, the
branch chiefs have been told to expect their budget to be about what it had
been the previous year for planning purposes. However, uncertainties in
funding levels have meant that the branch has planned only limited new work
related to CFS each year.
The branch's allocation memorandums for fiscal years 1994, 1996, 1997, and
1998 did not include an allocation for CFS research.15 That is, the
allocation forms, received more than 9 months into the fiscal year, did not
include any information about the level of funding available for the CFS
program. For fiscal year 1998, final clarification about funds for CFS was
not made until 9 days before the end of the fiscal year. Therefore, some CFS
funds were not obligated by the end of the fiscal year and some program
elements had to be suspended until the next fiscal year. However, in fiscal
year 1999, the allocation memorandum to the branch chief clearly outlined
the CFS funds available to the branch. This improvement may have been due to
changes CDC had instituted in response to the 1999 HHS Inspector General
review.
Finally, the Inspector General review reported that CDC said it could not
complete its adolescent study or hire a neuroendocrinologist because of a
lack of available funds.16 Nevertheless, the Inspector General found that,
while program components were not implemented, more than $850,000 of fiscal
year 1998 funds were never made available to the CFS program.
Research
NIH develops extramural research on diseases, including CFS, primarily by
creating program announcements for grant applications. The agency then
relies on external researchers to decide what topics they want to pursue and
funds meritorious applications up to the level of funds available. In
addition to using program announcements to encourage extramural applications
on CFS, NIH has created a special emphasis panel to review those
applications, used selective payment, and established CFS cooperative
research centers. NIH has also funded intramural investigations on CFS.
Intramural research is determined by individual researchers and reviewed
retrospectively. (See app. VIII for a more detailed description of these
efforts.)
Since 1987, NIH has issued four program announcements to stimulate research
on CFS. The first two program announcements were supported by NIAID only;
the first, in 1987, focused on epidemiology; the second, in 1992, focused on
exercise-induced fatigue and disease origin and development. In 1994, NIH
issued its first joint program announcement, involving three institutes,
which focused on studies of the causes, natural history, and origin and
development of CFS. The most recent program announcement, issued in 1996,
involves eight different units within NIH and supports studies on the
effects of CFS on the body.
NIH established the CFS Special Emphasis Panel to review CFS grant
applications. Agency officials reported that NIH did so to demonstrate the
agency's commitment to CFS research because CFS is so little understood and
so few applications for CFS were being received. The panels were designed to
help facilitate the consideration and scoring of CFS grant applications that
might otherwise not receive scores favorable enough to be funded if reviewed
by the regular review panels. To date, a total of 30 extramural grants (or
investigator-initiated research projects) reviewed by the panel have been
funded. During the years that CFS grants have been funded (fiscal years 1988
through 1999), the funding rate for CFS was about 24 percent versus about 28
percent for all grants across the same institutes that fund CFS research.
Officials at NIH have told us that, in their view, all meritorious CFS
applications have been funded and that review by the special emphasis panel
improves the chances that a CFS grant application will get a score that
qualifies it for funding.
NIH has also used selective payment to facilitate the funding of CFS
research. Selective payment is designed to provide funding to a small number
of applications that are programmatically important but not rated favorably
enough to receive funding otherwise. From 1992 through 1996, six CFS
applications were funded through this process--all by NIAID; however, none
have been funded through selective payment since 1996. NIH describes the
selective payment process as designed to support applications that received
scores just beyond the funding cut-off. However, it appears that NIAID made
extra efforts to fund some CFS research because CFS applications funded
through the selective payment process were ranked well beyond the funding
cut-off.17
Since 1991, NIH has also issued three separate requests for applications for
CFS cooperative research centers, supported with funds set aside for this
purpose. The centers are designed to augment the existing grant program and
to provide a sustained multidisciplinary approach to CFS research. The
intent is to advance the field by bridging basic science and clinical
research and facilitating confirmatory testing and follow-up of new
hypotheses and observations. An NIH official told us that, each year, the
agency plans to spend a certain amount on CFS. In fiscal year 1999, when NIH
was unable to spend these funds on grants (because few were approved for
funding), the agency chose to spend these funds on a third center, though
only two had been initially planned for.
In addition to these sources of support for extramural work on CFS, NIH has
also supported intramural work on CFS, most of it at NIAID. Intramural
research activities have included studies of chronic viral infections and
immunologic and endocrine systems. NIAID's intramural scientists have also
been involved in a number of other collaborative activities.18 Despite its
varied efforts, the intramural program on CFS in NIAID is currently
inactive. NIAID's primary CFS investigator has recently moved elsewhere in
the agency, and we were told that no one else has yet indicated an interest
in developing work in this area.
Researchers and patient advocates have also expressed concerns about the
extent to which the agencies obtain and use their input in developing
research programs and about how CFSCC functions to coordinate agency
efforts. While there has been interagency communication, coordination
between CDC and NIH and involvement of patient advocates and external
researchers have been limited. CFSCC has also had limited success in
ensuring a coordinated research effort.
External Researchers Limited
Although CDC and NIH officials reported frequent informal contacts, there
are few formal mechanisms for interagency coordination. The director of the
National Center for Infectious Diseases is an ex-officio member of NIAID's
National Advisory Allergy and Infectious Diseases Council, and NIAID's
Director of the Division of Microbiology and Infectious Diseases is an
ex-officio member of the National Center for Infectious Diseases' Board of
Scientific Counselors. Both advisory groups cover all areas of infectious
disease--not just CFS. Officials at both CDC and NIH claimed that
interagency coordination occurs through frequent and regular communication
about CFS across the two agencies. We were also told that these
communication efforts have been helpful and the quality of interagency
communication has improved in recent years.
However, there is little evidence of coordination between CDC and NIH on CFS
research. While the missions of the two agencies are somewhat distinct, we
identified no specific efforts to ensure that CFS research does not overlap
or leave important gaps. For example, while CDC and NIH-funded researchers
have shared preliminary manuscripts of their surveillance studies, both
agencies have separately funded community-based surveillance research. We
also identified no activities intended to build on the results of studies at
the other agency, beyond generally reading the scientific literature.
Further, there have been no joint CFS research projects undertaken by CDC
and NIH scientists. While CDC's peer review and Board of Scientific
Counselors both recommended that there be more collaboration, projects of
this type have not been initiated to date. CDC has indicated that it will
share blood and serum samples with NIH intramural and extramural scientists
when appropriate.
The agencies have used a number of mechanisms for soliciting the input of
external researchers and patient advocates. CDC included CFS patient
advocates on its two most recent CFS peer review teams, and NIH selected a
CFS patient advocate to serve 4 years on its National Advisory Allergy and
Infectious Diseases Council. Also, in 1998, patient advocates reviewed and
commented on CDC's revised patient brochure, and in 1999, CDC convened a
meeting of CFS patient advocacy group representatives to comment on various
aspects of the CFS program. Further, external experts comprise NIH's CFS
Special Emphasis Panel, reviewing grant applications.
However, the agencies have not always sought the input of patient advocates
and external researchers when there have been appropriate planning
opportunities. For example, NIH officials responsible for what was initially
intended to be a state-of-the-science meeting for CFSCC did not involve the
patient advocate and scientific members of the committee in the planning
process. This occurred despite the expressed interest of patient advocates
and researchers who had a number of specific concerns about the selection of
panelists.19
Coordinated Research Effort
While CFSCC has addressed a number of issues since it was chartered in 1996,
it has made only limited progress in meeting its goals aimed at improving
agencies' coordination of CFS research activities, programs, and education
efforts.20 Shortcomings in how the committee has functioned have hampered
its progress; some of these shortcomings are beginning to be addressed.
Some CFSCC efforts have helped facilitate communication--particularly among
representatives from FDA, the Health Resources and Services Administration,
and the Social Security Administration--about CFS activities that are being
carried out across HHS. For example, FDA used the CFS prevalence rates cited
by CDC to determine whether a product would qualify for orphan drug
designation.21 To help address some research and educational needs, CFSCC
identified gaps in knowledge and, in conjunction with their meetings,
scheduled scientific discussion around these topics, including adolescent
CFS issues and physician education. CDC officials also reported that the
agency provides funding to HHS' Health Resources and Services Administration
and a patient advocacy organization to develop CFS educational materials.
One CFSCC effort, currently under way, addresses patient advocates' concerns
regarding the term "chronic fatigue syndrome," which they believe does not
accurately reflect the nature of the disorder and stigmatizes individuals
diagnosed with CFS. To address this issue, CFSCC has surveyed physicians,
researchers, and patients and has formed a work group, with the involvement
of the Assistant Surgeon General and the support of the Assistant Secretary
of Health. CFSCC has also established a separate work group to review CFS'
placement in the International Classification of Diseases, an international
manual for classifying diseases. Committee consensus on this issue has not
yet been reached.
Overall, however, CFSCC has made only limited progress in meeting the goals
established by the Secretary to better coordinate CFS efforts. For example,
CFSCC has not been a particularly useful forum for developing complementary
research programs. At each of the committee's biannual meetings,
representatives from each agency have described their recent CFS activities,
but there has been little discussion about how to coordinate these
activities. Moreover, according to agency officials, the meetings have had
no effect on the direction of research at either CDC or NIH. However, agency
officials stated that a change in the direction of research generally occurs
as a result of relevant scientific or technical breakthroughs.
In addition, CFSCC has made only three recommendations to HHS'
Secretary--and none have focused on interagency coordination. The first
recommendation asked that HHS examine opportunities to combine existing data
from various sources to better understand prevalence and epidemiology; the
second asked the Secretary to help develop some clinically useful
instruments that could be linked to other CFS information; and the third
asked that the Secretary make more money available for CFS research to
attract more researchers to the field. Regardless of the focus of these
recommendations, the Secretary has not responded to any of them.
Patient advocates serving on CFSCC have voiced their dissatisfaction with
the committee's ability to get information from the agencies. Specifically,
they have been unable to obtain timely information from CDC and NIH
necessary to carry out their advisory function and to be responsive to
constituents. According to some of the patient advocate members, they
repeatedly requested from each agency, over separate time periods,
information on funding and research activities but did not receive the
information in a timely fashion.
Based on our discussions with agency officials and CFSCC members, as well as
a review of meeting transcripts, we found a number of shortcomings in the
way the committee functions that may be limiting its effectiveness.
Committee members cited a failure to
� discuss issues raised in agency reports and public testimony,
� develop recommendations for action, and
� develop continuity in the leadership of the committee because the cochair
alternates between CDC and NIH every 2 years.
Much of the committee's meeting time is spent presenting reports from each
agency on recent CFS activities. Minutes from the meetings show that, during
CDC and NIH agency updates, the agencies' representatives rarely, if ever,
questioned or discussed information in each other's updates. Meeting minutes
also reflect no discussion of the issues raised during the public testimony
portion of the meeting.
There are indications, however, that some of these shortcomings are
beginning to be addressed. NIH changed its committee representative--who
currently serves as cochair--from an official of NIAID to an official of
NIH's Office of the Director. CFSCC members cited this as a positive
development, viewing the centralized placement as more appropriate for
facilitating cross-institute communication. In addition, CFSCC, during its
February 2000 meeting, took steps to develop a new state-of-the-science
meeting, establishing a planning committee chaired by a scientific member.
This group will work between regular CFSCC meetings to facilitate more rapid
progress on developing the state-of-the-science meeting; it should also
provide greater committee control over the participants and agenda for this
meeting. Finally, the cochair has invited all committee members to submit
suggested format changes to make the meetings more productive. Some members
of the committee believe that format changes will provide for greater
discussion and progress and, therefore, coordination.
CDC has pursued avenues of research in a number of areas, in accordance with
the agency's mission and congressional report language, including work on
the case definition, surveillance, and risk factors for CFS. However, CDC's
funding practices and redirection of CFS funds have delayed its
research--evidenced by the agency's proposal to initiate an array of CFS
projects, funded with the money it plans to restore. NIH has used a number
of mechanisms to ensure that CFS research was funded. The development of
program announcements, creation of the special emphasis panel, the use of
selective payment, and support of cooperative research centers seem to
demonstrate NIH's commitment to CFS research.
CFSCC has not been successful in meeting its goal: to ensure interagency
coordination. While the committee has been useful in keeping both federal
agencies and the public informed of current developments at the agencies and
allowing the public an opportunity to raise issues that the committee might
want to consider, it has yet to stimulate much discussion about how CDC and
NIH could coordinate their programs. Recent actions within CFSCC to improve
the structure of the meetings should help the committee move toward
achieving its goals.
We provided HHS the opportunity to comment on a draft of this report. HHS
generally agreed with our findings and said that the report accurately
conveyed the department's efforts on CFS. HHS specifically agreed that CFSCC
could function more effectively as a coherent body with focus and direction.
The department also provided technical comments, which we incorporated where
appropriate. HHS' comments are reprinted in appendix IX.
As agreed with your office, unless you publicly announce the report's
contents earlier, we plan no further distribution until 30 days from the
date of this letter. We will then send copies to the Honorable Donna E.
Shalala, Secretary of HHS; the Honorable Jeffrey P. Koplan, Director of CDC;
the Honorable Ruth Kirschstein, Acting Director of NIH; and others who are
interested. If you have any questions or would like additional information,
please call me at (202) 512-7114. Marcia Crosse, Carolyn Feis, and Donald
Keller made major contributions to this report.
Sincerely yours,
Janet Heinrich
Associate Director, Health Financing and
Public Health Issues
Background on Chronic Fatigue Syndrome
Under the first U.S. CFS case definition, developed in 1988, a case had to
fulfill 2 major criteria and at least 8 of the 11 symptom criteria or at
least 6 of those symptom criteria and 2 of 3 physical criteria. One major
criterion was that there be a "new onset of persistent or relapsing,
debilitating fatigue or easy fatigability in a person who has no previous
history of similar symptoms, that does not resolve with bed rest, and that
is severe enough to produce or impair average daily activity below 50
percent of the patient's premorbid activity level, for a period of at least
6 months."22 The other major criterion was that other clinical conditions
capable of causing similar symptoms had to be absent upon a thorough
clinical evaluation. The list of the other conditions included over a dozen
broad categories of disease, such as malignancy, autoimmune disease, chronic
psychiatric disease, and chronic cardiac disease. The symptom criteria,
which also had to persist or recur over at least 6 months, were specifically
defined levels and/or kinds of fever, sore throat, sore lymph nodes, muscle
weakness, muscle discomfort, prolonged fatigue induced by exercise,
headaches, joint pain, neuropsychologic complaints, sleep disturbance, and
development of the symptom complex over a period of a few hours to a few
days (not a symptom but a criterion treated like the symptom criteria for
purposes of the case definition). The physical criteria were specific,
documented levels of fever, sore throat, and palpable or tender lymph nodes.
This first CFS case definition caused many difficulties for researchers. For
example, the definition did not appear to distinguish CFS from other types
of unexplained fatigue or define a distinct group of cases. As a result,
another CDC consensus panel revised the U.S. definition of CFS in 1994.
According to this second definition, in order to receive a diagnosis of CFS,
a patient case must satisfy two criteria: (1) severe chronic fatigue of 6
months or longer duration with other known medical conditions excluded by
clinical diagnosis and (2) four or more of the following symptoms
concurrently: substantial impairment in short-term memory or concentration;
sore throat; tender lymph nodes; muscle pain; pain in multiple joints
without swelling or redness; headaches of a new type, pattern, or severity;
unrefreshing sleep; and postexertional malaise lasting more than 24 hours.
The symptoms must have persisted or recurred during 6 or more consecutive
months of illness and must not have predated the fatigue. There are
currently no laboratory tests to diagnose CFS, and there are a number of
other illnesses that have a spectrum of symptoms similar to CFS, such as
fibromyalgia, myalgic encephalomyelitis, neurasthenia, multiple chemical
sensitivities, and chronic mononucleosis. Further, there are a large number
of other illnesses that can result in fatigue, the diagnosis of which would
preclude a diagnosis of CFS, such as major depressive disorders,
hypothyroidism, cancer, and others.
CFS does not appear to be as rare as was originally suggested. Table 1 shows
that estimates of CFS prevalence have increased over time as new data have
been obtained and the definition of CFS has been modified. The estimates
described here are based on data from samples of geographically defined
populations, as opposed to individual clinics or health groups, and are
based on patients who have been clinically evaluated relative to the case
definition--not on patients' self-identification of chronic fatigue. Early
CDC estimates--derived from data provided by physicians in four cities
(Atlanta, Georgia; Wichita, Kansas; Grand Rapids, Michigan; and Reno,
Nevada) who referred patients with CFS--were minimum prevalence rates, over
a 2-year period, ranging across cities from 2.0 to 7.3 per 100,000.23 A
subsequent report based on more data from the same sources yielded age-,
sex-, and race-adjusted rates over a 4-year period, ranging across cities
from 4.0 to 8.7 per 100,000.24 A more recent CDC study that looked only at
persons aged 18 to 69 in Wichita used a more valid community sampling
procedure to find cases, and had additional refinements of study design and
data analysis yielded an adjusted prevalence rate for 1997 of 183 per
100,000.25
When CDC reanalyzed the data from Wichita and included for the first time
complete data from certain participants whose data were initially
incomplete, the adjusted prevalence rate was reported to be 238 per
100,000.26 The research team that conducted a population-based study in
Chicago, funded by NIH, reported an overall estimated prevalence rate of 422
per 100,000.27 The estimated rate for women was reported to be even higher:
522 per 100,000.
Estimated number of
Study Methoda Rates (per people with CFS in U.S.
100,000)
population
Gunn and others
(1993), four 2-year prevalence 2.0-7.3 4,000-14,000
cities
Reyes and others
(1997), four 4-year prevalence, 4.0-8.7 8,000-17,000
cities adjusted
Reyes and others Prevalence,
(1998), Wichita adjusted 183 363,000
Reeves (1999), Prevalence,
Wichita adjusted 238 471,000
Jason and others
(1999), Chicago Prevalence 422 836,000
aAdjusted for age, sex, and race, where indicated.
There have been many hypotheses about the cause or causes of CFS. One
possibility is that an infectious agent, such as the Epstein-Barr virus, is
the cause of CFS, but a systematic association between CFS and Epstein-Barr
virus has not been found.28 Similarly, many known human infectious agents,
including other viruses and nonviral pathogens have been studied as possible
causes of CFS.29 So far, none of the infectious agents studied have been
found to be significantly associated with CFS. It is possible, however, that
an unknown or rarely studied infectious agent is the cause, or that CFS has
many different infectious causes, each one of which is responsible for only
a subset of CFS cases. Further, viral infection is one of many conditions
proposed, along with other transient traumatic conditions, stress, and
toxins, to trigger, but not necessarily sustain, the development of CFS.
Another vigorously pursued possibility is that CFS is caused by an
immunologic dysfunction, such as lower numbers of the immune system
components called "natural killer cells" or an inappropriate production of
the natural body chemicals known as "cytokines." Several immune system
abnormalities and histories of allergies have been observed in CFS patients,
but none of them consistently. Moreover, CFS patients have not been shown to
have the tissue damage found in autoimmune diseases, such as rheumatoid
arthritis. Nor do they typically manifest the susceptibility to
opportunistic infections or increased cancer risk so often found in persons
with deficient or suppressed immune systems, such as AIDS patients. It is
also possible that if there are immune system abnormalities in patients with
CFS, the abnormalities are themselves caused by infectious agents, other
specific kinds of exposure, or stress. There has been no empirical support
for any of these specific hypotheses involving an immunologic cause, but it
is possible that immunologic dysfunction plays a role, perhaps a complex
one, in the development of some or all cases of CFS.
The infectious and immunologic etiological hypotheses are not the only ones
that have been explored for CFS. Two hypotheses related to the nervous
system have also generated considerable research. First, it has been
observed that CFS patients secrete lower than normal levels of the hormone
cortisol in response to physical or emotional stress. The hypothesis that
has resulted from this observation is that the neuroendocrine system, which
is involved in these secretions via the hypothalamus and pituitary gland of
the brain (the hypothalamic-pituitary-adrenal axis), has an important role
in CFS. However, the difference in cortisol levels between patients and
healthy control subjects does not appear great enough to account for CFS.
Second, it has been hypothesized that disturbances in the autonomic nervous
system's regulation of blood pressure and pulse, characterized by abnormally
low blood pressure under certain circumstances, play an important role in
CFS. This condition is known as neurally mediated hypotension. As in the
cases of the infectious and immune system hypotheses, conclusive support for
the involvement of either the hypothalamic-pituitary-adrenal axis or
neurally mediated hypotension in all or most cases of CFS has not been
found.
Accounting Issues at CDC
In 1998, a CDC employee alleged that CDC had diverted CFS funds to other
programs and had provided erroneous information to the Congress regarding
the scope and costs of CFS research. At the request of CDC, HHS' Inspector
General conducted an audit to determine whether costs charged to the CFS
program from fiscal years 1995 through 1998 were actually incurred for that
program in accordance with applicable laws, regulations, and accounting
standards. CDC is not legally prohibited from spending funds budgeted for
CFS on other programs because the Congress did not make specific line item
appropriations to that program. However, it is clear from Senate, House, and
Conference report language that CDC was expected to spend the amount
budgeted for CFS only on CFS.
HHS' Inspector General found that a significant portion of CFS funds were
spent on other programs and activities and that CDC failed to adequately
document the relevance of other costs charged to CFS. The Inspector General
accepted 43 percent of the expenditures as actually incurred for program
purposes, could not accept 39 percent because they were incurred for
non-CFS-related activities, and could not determine the applicability of 18
percent of indirect costs because of insufficient documentation. The
Inspector General found that the questionable charges resulted from
deficiencies in CDC's internal control system for handling direct and
indirect costs. The Inspector General also found that, as a result, CDC
officials provided inaccurate information to the Congress.
The Inspector General further determined that CDC did not have adequate
controls to ensure that direct costs charged at the program activity level
are based on the actual efforts of involved personnel. As a result, the
Director of the Division of Viral and Rickettsial Diseases was able to
transfer to CFS unrelated costs without appropriate analysis, documentation,
or justification. Similarly, the Inspector General determined that CDC had
inadequate controls to ensure that indirect costs from all organizational
levels were properly identified and consistently allocated.
In response to the Inspector General report, CDC will restore $12.9 million
in funding to the CFS program over 4 years. This is identical to the sum of
funds the Inspector General did not accept as related to CFS ($8.8 million)
and was questionable ($4.1 million). CDC also promised a number of
corrections:
� A public apology to the Congress from the Director of CDC and other senior
staff.
� Probationary status for the Division of Viral and Rickettsial Diseases
with regard to budget execution until January 2001.
� Separate apportionment of CFS funds from the Office of Management and
Budget with the accompanying requirement that an operating plan be submitted
to the Congress. Accordingly, quarterly reports will be submitted to the
Congress regarding the budgetary execution of this plan.
� Mandatory training for all CDC managers and staff responsible for budget
and accounting functions to ensure complete knowledge of statutory and
regulatory requirements for the use of federal funds.
� Establishment of an internal review capacity to conduct regular
assessments of CDC's fiscal policies, procedures, practices, and controls.
� Development and implementation of a new system for allocation of CDC-wide
indirect program support costs.
� Reinvigoration of CDC's efforts to better understand CFS by establishing a
long-term research and program agenda with in-depth advice from the research
and advocacy communities.
A subsequent accounting analysis of fiscal year 1999 CFS expenditures,
conducted by PricewaterhouseCoopers, an independent auditing firm, found
that 99.2 percent of the fiscal year 1999 funds reported by CDC as CFS
obligations were in fact related to CFS program activities. They also found
that CDC adequately addressed the concerns raised by the Inspector General
report for the CFS program for fiscal year 1999.
In February 2000, there were public reports that similar accounting
difficulties extended beyond the CFS program. Specifically, it had been
reported that CDC also spent funds intended for the study of hantavirus on
other diseases. The PricewaterhouseCoopers analysis of fiscal year 1999 CFS
expenditures also recommended that the CDC strongly consider conducting an
accounting analysis of the obligations reported for the hantavirus program
for fiscal years 1995 through 1998. In response to these concerns, CDC made
management changes at the level of the Director of the Division of Viral and
Rickettsial Diseases, responsible for both the CFS and hantavirus programs.
In addition, the Secretary of HHS, in consultation with the Director of CDC,
told the Congress that a number of additional corrective actions were under
way:
� HHS' Chief Financial Officer will take such actions as necessary to
certify all financial obligations made by the National Center for Infectious
Diseases for the remainder of fiscal year 2000.
� HHS' Chief Financial Officer will work with the Director of CDC to ensure
that all senior decisionmakers in the National Center for Infectious
Diseases receive certified budget execution training.
� CDC is commissioning an external review of the agency's fiscal management
practices. The review is to be completed by September 2000. The results of
the analysis will be communicated to the Congress as soon as the review is
complete.
� CDC program managers will conduct a top-to-bottom examination of CDC's
programs and projects to make sure there are no other areas of concern.
During the 90-day period, CDC managers will be able to fully and openly
identify any area for which there may be a discrepancy between actual
expenditures and the information provided to the Congress. CDC will share
these findings with the Congress.
� CDC has commissioned PricewaterhouseCoopers to thoroughly examine the
hantavirus expenditures. The results will be communicated to the Chair of
the Senate Subcommittee on Labor, Health and Human Services, Education and
Related Agencies, Committee on Appropriations, immediately upon completion.
When the audit is complete, CDC will expand the effort to the entire
National Center for Infectious Diseases.
CDC Research Efforts and Publications
CDC, with others, developed the first case definition of CFS in 1988 and the
second definition in 1994. These case definitions reflect clinical judgment
gathered from experience with patients sick enough and with sufficient
resources to seek medical care. Neither of the case definitions has been
derived from quantitative clinical data, such as lab results, because there
are no known markers for infection and, consequently, no laboratory tests
available. CDC recently met to consider the need for another revision of the
case definition, which may change the number of people who could be
diagnosed with CFS, as occurred when the definition was broadened in 1994
and more people met the revised definition's criteria. While higher
prevalence estimates can be helpful to research by potentially attracting
more funding and more research interest, it can also mask possible research
findings--that is, if the population now defined as having CFS is
heterogeneous, it may be more difficult to identify causes.
CDC has conducted a number of surveillance studies to determine the
prevalence of CFS, including a four-city study using physician referrals to
identify possible CFS patients. CDC was criticized for using physician
referrals because patient frustration over physicians who do not understand
CFS or over insurance difficulties may result in CFS patients not being in
the health care system. A CDC official offered many justifications for this
approach, including its past use for other diseases, the participation of
most primary care physicians in the areas studied, and the ability to gather
data annually. Further, we were told that the study was the most rigorous
that could be performed with the funds that were available to the agency at
that time and that the prevalence estimates could be used to estimate the
burden of CFS on the health care system.
CDC shifted from this passive surveillance approach to a more active
approach when it conducted a pilot study of randomly selected individuals in
San Francisco, California. Based on this pilot, the agency began a
large-scale study in Wichita, Kansas. Here, almost 7,000 subjects are being
followed annually for 3 years. However, because most participants in the
Wichita sample are white, the sample may not be adequate for studying the
prevalence of CFS in racial and ethnic minorities. Regardless, a CDC
official told us that Wichita was chosen because it is representative of the
United States with respect to its racial and ethnic makeup. Further, the
population of Wichita is relatively stable, allowing for the long-term
follow-up called for by the study. CDC uses interview and clinical data from
participants in these studies to describe the epidemiology of fatiguing
illnesses. For example, blood and other specimens are collected from those
enrolled in the clinical evaluation component of the study to be used in
laboratory studies to identify risk factors and diagnostic markers. CDC is
also taking additional steps to estimate prevalence. The agency is currently
developing a national study to estimate sex-, age-, race/ethnic-, and
socioeconomic-specific prevalence of CFS. Finally, late in fiscal year 2000,
CDC plans to begin developing a national CFS patient registry where patients
will be followed yearly.
To date, CDC studies of risk factors and diagnostic markers associated with
CFS have not identified consistently strong and significant associations
between CFS and exposure to infectious agents or abnormalities in immune
function.30 In efforts to understand the physiological basis of CFS, CDC
established a group to examine genetic issues in CFS and further identify
risk factors and diagnostic markers. CDC also has investigated suspected
clusters of CFS in seven different locations but was unable to confirm any
clusters in these areas.
CDC has presented only limited data on the natural course of the disease,
relying on data collected from their longitudinal surveillance studies,
which have taken years to conduct. Further, CDC has acknowledged the
limitations in the data it has published from its four-city physician-based
study. CDC has noted that the study was limited because most patients had
been ill for many years and no clinical data were gathered to further
support the symptoms described by patients, observed by providers, or both.
To supplement this work, CDC continues to gather data from the Wichita area
that include baseline and annual follow-ups for 3 years.
CDC has undertaken a variety of efforts to educate practitioners,
professionals, and the public. Scientists from CDC have published numerous
articles describing their work, and a CDC official reported that
peer-reviewed publications, listed in figure 4, were the cornerstone of
their education efforts for physicians.
Source: CDC.
In addition, CDC has established a web site devoted to CFS containing
hundreds of pages of materials, has maintained a toll-free hot line, and has
developed a booklet about CFS, which has been revised twice. Further, CDC
has presented information at conferences for CFS patient support groups and
other professional associations. CDC acknowledges that some physicians might
not recognize CFS as a distinct illness. As a result, CDC plans to add a
medical education specialist to its staff in fiscal year 2000 to develop a
more rounded and aggressive medical education program aimed at health care
providers, public health officials at the state and local levels, health
maintenance organizations, and insurance providers.
CDC has been criticized for delays in releasing the findings of its studies
and for the breadth of its research. CDC sometimes does not release findings
from its studies until they are published in a professional journal. The
publication process can take months or years, meaning that the latest
information may not always be immediately available. However, CDC officials
told us they use professional journals to communicate with the medical
community--the generally accepted way to disseminate results from scientific
studies. Further, the peer review that is often required prior to
publication can serve to validate its findings. Second, some scientists feel
that certain areas of research have not been adequately or appropriately
pursued. For example, some were concerned that valuable data would be lost
when CDC proposed selecting new patients for future work, rather than
continuing to work with those patients who had been part of the Wichita
study for 3 years. In addition, it has been suggested that CDC's efforts to
replicate findings on certain types of viruses did not use the same
methodology as in the original study and, therefore, CDC's failure to
replicate the findings was based on a flawed design. CDC officials stated
that the agency plans to continue working with patients identified during
the Wichita study as part of future clinical and laboratory investigations.
CDC officials also reported that the agency uses the most current and
appropriate methods to identify infectious agents. According to agency
officials, where these differ from those in an original study, it is because
CDC has determined new or better methods exist.
NIH Research Efforts and Grants
The National Institute of Allergy and Infectious Diseases (NIAID) has
pursued the goal of studying the causes of CFS, including the search for
risk factors and diagnostic markers, more extensively than any of its other
CFS-related goals. A number of the other institutes have supported
collaborative or complementary work on causes. NIH has funded investigations
of immunologic, neuropsychologic, neuroendocrinologic, brain wave, and
infectious aspects of CFS, any of which might have implications for
understanding causes.31 Studies of subtypes of CFS have also been conducted.
Although CDC has taken the lead in efforts to estimate the prevalence of
CFS, NIAID has also supported a number of attempts to establish the
magnitude of the problem. In the early 1990s, it funded research in Seattle
and Boston estimating CFS prevalence in primary care settings. In 1995, it
began funding a large epidemiological project in Chicago to study the
socioeconomic and ethnic variability of CFS. This project has generated
population-based prevalence estimates for the overall population and for
racial and other subgroups, such as women.
NIH has supported research on the origins and development of CFS. Early work
focused on the possible role of Epstein-Barr virus in CFS and on certain
immune system deficiencies thought to occur in CFS. The two most recent
efforts involve a model of postinfectious fatigue, which may provide insight
into what happens when a person contracts CFS after an infection, and blood
pressure irregularities in CFS patients.
NIH has supported some efforts to develop clinically useful diagnostic
methods. The early work in this area involved distinguishing chronic, active
Epstein-Barr infection from diagnosed CFS. More recently, NIH has supported
a study of the effective diagnosis of chronic fatigue and its intensity and
a study of the feasibility of using specific measurement tools to evaluate
CFS patients.
NIH has supported several projects with possible application to treatment.
These include modulating brain chemistry and developing individually
tailored exercise programs. Other efforts have included trials of
pharmacologic agents and studies of nonpharmacologic treatments.
Work on NIAID's goal of furthering prevention would be premature given the
limited understanding of the causes of CFS, and NIH has not supported
efforts in this direction. However, NIH has supported a number of relevant
efforts not explicitly linked to any of its stated goals, such as activities
contributing to the education of researchers--chiefly workshops and other
kinds of meetings--and to a lesser extent, the education of practitioners
and the public, chiefly pamphlets about CFS.
Researchers and patient advocates have criticized NIH's efforts on CFS
research. Some have suggested that studies in certain areas have not been
adequately investigated. In at least one situation, it has been speculated
that NIH investigators did not pursue a particular finding because the
finding was possibly contrary to what was expected. We were also told that
prominent researchers have been turned down for funding, discouraging them
from staying in the field. Some patient advocates have argued that NIH is
increasingly funding research on mental health and its relation to CFS, but
the evidence does not support this assertion. While it appears that the
National Institute of Mental Health has spent more funds on CFS research
than any institute other than NIAID, this is an artifact of the data
management system at NIH. The majority of these funds were allocated to a
study encompassing a range of work, only a small portion of which was
related to CFS. In fact, National Institute of Mental Health officials told
us that they do not consider CFS to be a mental disorder and that CFS is not
listed in the diagnostic manual used in psychiatry and psychology. They
further do not consider themselves to have an ongoing program on CFS; rather
they occasionally study CFS because of interest in certain relevant
hypotheses. Nevertheless, these concerns are indicative of the doubt and
mistrust that both researchers and patient advocates expressed.
Due to concerns we heard about inconsistencies between CFS grants listed in
NIH reports and grants listed in NIH's Computer Retrieval of Information on
Scientific Projects (CRISP), we conducted our own search of CRISP. Using
only the key phrase "chronic fatigue syndrome" for years 1997 through 1999,
we searched CRISP and found a number of studies that were not included in
the lists of grants originally provided to us by NIH.
NIH officials explained this discrepancy. Projects identified through CRISP
are based on text word searching and, as such, are not verified as
rigorously as are projects for budget and research reporting, including the
CFS grant tables provided to us. Due to the indexing terms used for CRISP
and the search logic employed, it is not unusual to observe differences
between CRISP-generated lists (which are designed for public access) and
formal agency reporting related to fiscal responsibility. According to
agency officials, the primary reason for differences between the list of
projects found through CRISP and the list of projects reported by the
institutes is that the methods used to compile the lists are different.
Entering a set of key words in CRISP will generate a list of projects based
on the grant application. The institutes may use CRISP as a starting point,
but the institutes have procedures to ensure that they report to the budget
office only actually funded projects or subprojects. For example, in a large
center grant, the CRISP database may include a number of subprojects. Some,
but not all, of these subprojects may be related to the specific disease
area in question. Occasionally, a planned subproject will not be funded.
Such a subproject would not be included in the list of projects generated by
the institute but could remain in the CRISP database (see table 2).
NIH disposition Number
Projects should have been included
Small business innovative research grants (grants were not included
in NIH's search for CFS grants) 1
Grants funded for a year in addition to that included on the list
of projects provided by NIH 1
Subproject of a general clinical research centers grant 4
Subproject of a biomedical resource grant 1
Grants inadvertently not included in NIH list, identified by NIH
prior to this request 1
Projects were appropriately not included
CFS was not the primary focus of the grant 6
Subproject of a grant, funding of subproject reported in funding of
overall project 1
Cooperative Research Center (subproject reported in CRISP by a
different title than by NIH) 6
Project in CRISP had a different title than that on list provided
by NIH 2
Project number duplicated an earlier grant 1
Project was not funded during one of the years for which it was
listed in CRISP 1
Tables 3 through 6 list all CFS-related NIH-funded grants and projects,
which are administered through the following institutes:
� National Cancer Institute (NCI),
� National Center for Research Resources (NCRR),
� National Heart, Lung, and Blood Institute (NHLBI),
� National Institute of Allergy and Infectious Diseases (NIAID),
� National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS),
� National Institute of Child Health and Human Development (NICHD),
� National Institute of Mental Health (NIMH), and
� National Institute of Neurological Disorders and Stroke (NINDS).
Fiscal Total funding in
year(s) Institute Grant title dollars
1987-1990 NIAID Definition of the Chronic $540,220
Epstein-Barr Virus Syndrome
1989-1991 NIAID Prevalence of CFS 930,285
1990-1992 NIAID Neuroimmunologic Studies of CFS 871,215
1992-1994 NIAID Chronic Fatigue in Lyme Disease 744,236
1992-1994 NIMH Predictors of Recovery From 716,106
Acute Viral Infectiona
1993-1997 NIAID Human JHK Virusb 769,203
1993-1995 NIAID Exertion-Induced Cytokines in 536,958
CFSb
1993-1995, Motor Control and Cytokines in
NIAID CFS (later retitled Motor 970,696
1997-1999 Control in CFS)b
1993-1995 NIAID Exercise Intolerance in CFS 454,121
1993-1999 NIMH Research Center on the 6,978,751
Psychobiology of Ethnicityc
1993 NIAID Virology Assessment of CFS 6,910
Patientsd
1993-1996 NIAID Antigens of Human Herpesvirus-6 521,694
1994-1996 NIAID Virology and Immunology of CFSb 497,473
1994-1996,
NIAID Mechanisms of Immunologically 1,008,464
1998-1999 Mediated Fatigue
1995-1999 NIAID Estimating Rates of CFS in a 2,714,041
Community Sample
Transforming Domain of Human
1995 NCI Herpesvirus-6 That 207,000
Transactivates HIV 1
1995 NCI Epidemiologic Study of Pediatric 55,000
HIV-Related Lymphomas
Molecular Studies on Bovine
1995 NCI Immunodeficiency Virus and 21,000
Bovine Herpes Virus Interactions
1996-1998 NIMH Cognitive Dysfunction in CFS 275,836
Dysregulated 2-5A
1996-1999 NIAID Synthetase/RNase L/PKR Pathways 1,086,909
in CFSe
1996-1998 NIAID A Trial of Fludrocortisone for 748,132
CFSb
1997-1999 NIAID Autoantibodies to Cellular 1,063,378
Matrix Antigens in CFS
1997-1999 NIAID Mechanisms of Rhinitis in CFS 508,806
1998-1999 NIAID A Model for Induction of CFS 641,607
1998-1999 NHLBI Circulatory Control in Young 859,156
People with Chronic Fatigue
1998-1999 NHLBI Investigation of Orthostatic 639,674
Intolerance in CFS
1998-1999 NIAMS HPA Axis Dysregulation in 385,015
Fibromyalgia
Auditory Working Memory in CFS:
1999 NIMH A Functional Magnetic Resonance 135,152
Imaging Study
1999 NHLBI Muscle Blood Flow and CFS 114,359
Motor Learning in CFS:
1999 NINDS Implications for Neural 160,665
Dysfunction
Total funds $25,162,062
aThis NIMH grant was funded prior to the time when NIMH was a part of NIH,
but the project extended into the period after which NIMH was a part of NIH.
Therefore it is included.
bGrant funded through selective pay program.
c This NIMH project studies a range of issues and only a small portion of
the funds are spent on CFS-related activities.
dFrom 1991 through 1995, this project was also a subproject to a cooperative
research center project (see table 5). During fiscal year 1993, the project
was also supported with an R01-type Research Project grant.
eThe first-year funding for this grant was under exploratory/developmental
grants.
Fiscal Total funding
year(s) Institute Grant title in dollars
1987-1988 NIAID Study of Sporadic Neurasthenia $928,400
Associated With Epstein-Barr Virus
1989-1996 NIAID Chronic Epstein-Barr Virus Infection 6,001,482
and CFS
1991-1995 NINDS Neuropsychological Investigations of 30,234
Human Cognition and Mood State
1991-1993, CNS Role in the Susceptibility to
1995 NIMH Inflammatory Illness 428,000
Combined Clinical, Viral, and
1992-1993 NINDS Immunological Studies of 6,125
Neuromuscular Diseases
Epidemiology Studies and Basic
1993-1994 NCI Research Related to CFS Outbreaks and 399,000
Characterization of the Viruses
Associated With CFS
Support for Physicians Treating CFS
1993-1994 NCI Patients by the National Physicians 706,000
Advisory Group
1993,
1995-1999 NIMH Neurobiology of Unipolar Depression 1,033,808
Dose-Response Relationships for
Single Doses of Recombinant Human
1994, 1998 NICHD Interleukin-6 in Normal Volunteers 30,000
and in Patients With Disorders of the
Hypothalamic-Pituitary-Adrenal Axis
1995 NCI Identification of Human Genetic Loci 115,000
Which Influence Susceptibility to HIV
1995 NCI Regulation of Viral and Cellular Gene 30,000
Expression
1995 NCI Genetic Variation in Infected 30,000
Hemophiliacs Over Time
1997-1998 NIAID Multidisciplinary Studies of CFS 1,795,181
1997-1999 NIAID Trial of Fludricortisone for Patients 524,488
With CFS
Total funds $12,057,718
(Continued From Previous Page)
Fiscal Total funding
year(s) Institute Grant title in dollars
1987-1996 NIAID Pathogenesis of Epstein-Barr Virus $2,896,620
Infections
1989 NCRR Prevalence of CFS in Ambulatory 3,949
Medicine
1989 NCRR Immunologic and Virologic Studies of 188
CFS
1990 NCRR Sleep and Cytokines in CFS 21,178
1990 NCRR Involvement of a Human Retrovirus in 8,531
CFS
1990 NCRR Analysis of Clinical and Biological 350
Characterization of CFS
1991 NCRR Psychology and Immunology of CFS and 2,609
Other Disorders With Severe Fatigue
1991 NCRR Acute Experience: Stress and Immune 3,447
Function in CFS Patients
1991-1992 NCRR Ampligen in Patients With CFS and 103,584
Associated Encephalopathy
1992-1993 NCRR Electroencephalogram Sleep in CFS 6,170
1993-1996 NCRR Exertion Induced Cytokines in CFS 147,883
Coordinating Center for Clinical and
1993, 1996 NIAID Epidemiologic Studies in Infectious 21,567
Diseases
1993-1997 NIAID Social Processes and 625,463
Somatization--The Course of CFS
1993, Phosphocreatine Recovery in Women
1995-1999 NCRR With CFS 111,802
1994-1995 NIAMS Cytotoxic T Lymphocyte Mediated 185,399
Cutaneous Immunity to Melanoma
1994-1995 NIAMS Molecular Basis of T-Cell Helper 92,610
Function
1994-1995 NIAMS Molecular Determinants of 171,203
Epstein-Barr Virus Tropism
1995-1996 NCRR Neuropsychological Disturbance in CFS 65,584
1995-1997,
1999 NCRR Exercise Intolerance in CFS 44,027
1995 NCI Viruses and Oncogenes in 102,000
Hematopoietic Malignancies
In Vitro Effects of Interleukin 2 on
1996 NCRR Activity of Natural Killer Cells in 273
CFS
1996 NIAID Operations and Technical Support 444,673
Clinical Application of
1996 NCRR Deoxymyoglobin Technique: Peripheral 28,718
Vascular Disease or CFS
1996 NIAID 1996 Scientific and Clinical Meeting, 2,000
CFS
Microbial Genomic Sequencing in
1996 NCRR Emerging Disease With Unknown 121,392
Etiology: Kawasaki, CFS
1997-1998 NCRR Hypothalamic-Pituitary-Adrenal Axis 130,814
Dysregulation in Fibromyalgia
1997 NCRR Comparative Study of Pathophysiologic 1,912
Descriptors of CFS
1997-1998 NCRR Trial of Fludrocortisone for CFS 25,119
1997-1998 NCRR Regulation of Adrenal Function in 129,609
Fibromyalgia
1997 NCRR Immunoneuroendocrine Response to 19,690
Tetanus Toxoid
Psychiatric Diagnosis and Biological
1998 NCRR Markers in Neuresthenia, CFS, and 18,516
Depression
1998 NIAID CFS in Adolescents, Workshops 12,855
1999 NCRR Mitochondria in CFS Pathology 178
1999 NCRR Models for Induction of CFS 18,933
1999 NCRR Psychoimmunological and 315
Neuroendocrinological Response
1999 NCRR Mechanisms of Rhinitis in CFS 47,865
1999 NCRR Skeletal Muscle in Persian Gulf 21,009
Veterans With CFS
1999 NIAID Diagnosis and Treatment of CFS 250,000
1999 NIAID Venous Dysfunction in CFS 73,247
1999 NIAID Siberian Ginseng for the Treatment of 67,827
CFS
Total funds $6,029,109
(Continued From Previous Page)
Fiscal Total funding in
year(s) Grant title dollars
Brigham and Women's Hospital (1991-1995)
1991-94 CFS, Fybromyalgia, and Depression $949,384
1991-94 Cytokines and CFS 543,244
1995 Core A 100,001
National Jewish Center for Immunology/Resp. Med. (1992-1995)
1992-94 Clinical Research on CFS and 411,666
Quantification of Fatigue
1992-94 Developmental Research on CFS and 56,248
Quantification of Fatigue
1992-95 Quantification of Fatigue in CFS 307,404
1992-95 Allergic Inflammatory Reactions in CFS 414,161
1992-95 Neurophysiologic Disturbance in CFS 486,392
1992-95 Neuropsychiatric Features of CFS 374,651
University of Medicine and Dentistry of New Jersey (1991-1995, 1995-1998,
1999-present)
1991-95 Classification of CFS Patients 1,533,813
1991-95 Virology Assessment of CFS Patients 568,659
1991-94 Immunological Assessment of CFS Patients 586,658
1995-98 Administrative and Data Analysis Core 841,868
1995-98 Categorization of CFS Patients 1,675,787
1995-98 Exercise, Fatigue, and Training 1,209,745
1999 Brain and Cardiovascular Studies 302,089
1999 Physiological Challenges in CFS 203,178
1999 Statistical and Data Core 238,008
University of Washington (1995-1998, 1999-present)
1995-99 Clinical Core 321,819
1995-98 CFS: Neuropsychological, Neuroendocrine, 493,145
Sleep Function
1995-98 Immunology and Virology of CFS in 662,290
Monozygotic Twins
1995-98 Biological/Psychosocial Factors: 490,453
Post-Infectious Fatigue
1995-98 Prognosis of CFS 525,887
1999 Monozygotic Twins With CFS--Predisposition 269,612
of Perception
1999 Population Based Twin Study of CFS 202,822
1999 Biostatistical and Data Management 140,142
1999 Children of CFS Patients 140,082
University of Miami (1999-present)
1999 Cognitive-Behavioral Stress Management 136,299
Intervention for CFS
Effect of Stress and Cognitive-Behavioral
1999 Stress Management on Natural Killer 61,147
Activity in CFS
1999 Laboratory Assessment 153,311
Total funds $14,399,965
Congressionally Requested CFS Activities for CDC and NIH
CDC has initiated work on most CFS activities requested in congressional
committee report language. However, procedures for ensuring that the branch
chiefs responsible for the work were aware of congressional expectations
have only recently been established. Agency officials reported that while
CDC has distributed to the centers the relevant portions from House, Senate,
and conference appropriations reports, it has only been since the arrival of
an associate director for management at the Division of Viral and
Rickettsial Diseases in 1997 that this report language has been disseminated
to the division's branch chiefs responsible for planning the research.
Of the 33 requested CFS activities, 3 are planned for this fiscal year (see
table 7). CDC reports that it plans to initiate a national survey in 2000,
but it is unclear that this will include a surveillance component as
suggested in congressional committee reports in 1998. CDC also reports it
will begin planning for the establishment of a CFS patient registry in
fiscal year 2000 as suggested by report language in 1991. This patient
registry will also allow CDC to address the third area of congressional
interest, suggested in 1997: developing a CFS brain tissue repository.
(Continued From Previous Page)
Activity requested Year(s) Year(s)
requested started
Develop and implement a surveillance
network. 1988 1988
Expand surveillance system to all states. 1988 a
Increase level of research support. 1988 1988b
Work with Nevada. 1988 1990
Expand sentinel surveillance. 1989, 1990 1990
Expand study on link between CFS and human
herpesvirus-6. 1989 1992
Continue attempts to detect persistent virus
infections in CFS patients and to develop 1989 1992
appropriate controls.
Expand surveillance to Nevada. 1989 1990
Enroll patients in case studies. 1990 1990
Investigate suspected clusters. 1990 1985
Train and educate physicians and health
workers about CFS. 1990, 1998 1990
Develop information for the general public
to increase the general understanding of 1990 1990
CFS.
Expand research on immunologic
abnormalities. 1990 1992
Provide CFS information, outreach,
conference, and training activities. 1991 1991
Refine CFS definition. 1991 1991
Study the establishment of a CFS patient
registry. 1991 2000c
Develop recommendations to the U.S.
biomedical community on standardized
clinical data collection instruments and 1991, 1992 1994
procedures for evaluating functional health
status in CFS.
Advise on the establishment of standardized
protocols for CFS laboratory tests. 1991, 1992 1994
Store serum and leucocyte samples from CFS
patients for future testing. 1991, 1992 1992
Expand immunological, virological, and
toxicological studies of CFS. 1993 1992
Expand CFS research activities, including
research on the relationship of CFS to
pregnancy, a study of CFS patients in
remission to monitor the long-term effects 1993 1994d
of the disease, and research on the impact
of CFS on health professionals.
Make available to interested parties
preliminary and pending data related to the
CFS surveillance system, data from the
case-control study that began in June 1992, 1993 1990e
and data related to CDC responses to cluster
outbreaks of CFS.
Expand the surveillance system to 8- to
18-year-olds 1993 1992
Conduct community-based prevalence studies
to collect data on endemic cases and
possible cluster outbreaks and to document 1995 1993
the basic epidemiology of CFS.
Support four studies on possible
transmission routes, especially among health
care workers, family members, and maternal 1995, 1996 f
transmission to unborn children.
Provide education programs, as appropriate. 1995, 1996 1997
Complete and expand current CFS surveillance
projects. 1996 1996
Commence a case-control phase of the
community-based surveillance study recently 1996 1997g
completed in San Francisco.
Consider implementing the review panel's
recommendations, particularly in the areas
of etiology studies and brain tissue 1997 1996, 2000h
repositories.
Enhance CFS laboratory studies and
surveillance projects, including outreach to
populations not previously recognized as 1998, 1999 1997
being affected by CFS, especially
minorities, children, and adolescents.
Encourage continuation and expansion of
studies of adolescents and children. 1998 1993
Add a neuroendocrinologist to research
group. 1998, 1999 1999i
Initiate studies on rates of CFS among
health care workers, family members of CFS 1998 1994d
patients, and pregnant women.
aNational survey planned for 2000.
bFunding levels show an increase since 1988.
cMeeting planned.
dDoes not include pregnant women.
eFindings presented.
fCDC has found no evidence that CFS is transmissible.
gData used as pilot of Wichita study.
hEtiology studies began in 1996; brain tissue repositories in 2000.
iHiring in process.
Within these activities, however, CDC is not pursuing or considers
infeasible the following areas of congressional interest: investigating the
relationship of CFS to pregnancy (part of an activity requested in 1993);
supporting four studies of possible transmission routes (requested in 1995
and 1996); commencing a new phase of the community-based surveillance study
completed in San Francisco that compared CFS patients to healthy controls
(requested in 1996); and initiating studies on the rates of CFS among
pregnant women (part of an activity requested in 1998). CDC reported
justifications for a number of these unaddressed areas. For example, the
agency has not conducted and does not anticipate studying pregnant women
because the low age-specific prevalence rate suggests that pregnant women
would rarely be affected and human subjects and ethical considerations
preclude such studies. Further, while it has conducted studies of
transmission since 1985, the agency was not aware of the four transmission
studies referred to in the report language. Finally, while the San Francisco
study was used as a pilot for the Wichita surveillance study, CDC reported
that it was not possible to compare CFS patients with healthy individuals in
San Francisco due to the nature of that study.
NIH has been asked to pursue CFS work in 34 areas by congressional
appropriations committees (see table 8). Five activities have not been
pursued or are considered by NIH to be infeasible: expand research in
identification of eventual cure (requested in 1988); expand research on
genetic disposition and allergy, immune and neurological systems (requested
in 1991); designate reference laboratories for CFS (requested in 1991);
compile a CFS patient registry (requested in 1992); and address care needs,
including the education of providers in assessment, diagnosis and treatment,
case management, and rehabilitative efforts (requested in 1999).
NIH reported that all CFS research efforts are designed to find an eventual
cure. However, because so little is currently known about CFS, the agency
has not reported any specific activities directly related to a cure
(although it has initiated some studies of possible treatments) or to direct
linkages between genetic disposition and allergy, immune, and neurological
systems. NIH considered establishing a CFS patient registry but determined
that it was not feasible and that it was more part of CDC's purview.
Finally, NIH reported to the appropriations committees that the language
regarding care needs was more appropriate for HHS' Health Resources and
Services Administration.
(Continued From Previous Page)
Activity requested Year(s) Year started
requested
Expand research in search for a diagnostic
technique. 1988 1992
Increase efforts to discover cause and
treatments. 1988, 1994 1991
Expand research in identification of an
eventual cure. 1988
Consider use of the small grants program
for research on the chronic Epstein-Barr 1988 1991
virus syndrome.
Locate additional research in Nevada. 1989 1991
Conduct research on understanding and
correcting immune system damage. 1990 1991
Study the feasibility of establishing a
research center for CFS studies, including
collecting and analyzing clinical and 1990 1991
laboratory data on patients.
Issue a request for applications on CFS to
increase the number of extramural research 1990 1991
grants funded.
Solicit and fund additional research
grants. 1991 1991
Initiate a consortium of research centers
for CFS research, preferably at the 1991 1992
Universities of Nevada and Minnesota.
Expand research with other institutes. 1991 1991
Expand biomedical meetings. 1991 1992
Increase extramural and intramural research
studies. 1991 1991
Report annually to the Congress on
activities related to CFS. 1991, 1992, 1993 1991
Conduct a conference in fiscal year 1991 on
NIH activities related to CFS. 1991 1991
Expand research on genetic predisposition
and allergy, immune, and neurological 1991
systems.
Designate reference laboratories and
facilitate data exchange among institutions
in the geographic areas in which CFS 1991
concentrates.
Designate a senior agency official to act
as CFS coordinator. 1991 1991
Establish a multidisciplinary study section
for CFS. 1992, 1993 1993
Establish a standing study section for CFS. 1993 1993
Compile a CFS patient registry. 1992
Study the feasibility of establishing a
central clearinghouse for CFS data . 1992 1992
Make grants to, or enter into contracts
with, public or nonprofit entities for the
development and operation of centers to 1993 1993
conduct basic and clinical research on CFS.
Ensure that individuals who have expertise
in CFS or neuromuscular diseases and are
representative of a variety of disciplines 1993, 1998, 1999 1993
and fields are appointed to appropriate NIH
advisory committees and boards.
Establish procedures to enable the patient
community to provide input to the direction 1993 1993
of CFS research at NIH.
Consider increasing opportunities for CFS
patients and researchers to participate in 1993 1993
advisory committees.
Conduct studies that continue to look into
retrovirus activity and other areas of 1994 1994
infectious disease pathogenesis.
Direct resources to extramural grants
focused on promising areas of biomedical
research and to investigations seeking to 1996, 1998 1996
identify etiological agents and markers for
the pathophysiology of CFS.
Appoint a CFS coordinator with NIAID-wide
authority. 1996, 1998 1996
Include other agencies, such as CDC and
HHS' Health Resources and Services
Administration, in the planning and 1998 1998
execution of the workshop on pediatric CFS.
Recommend that the Office of Research on
Women's Health develop a strategy to 1998 1998a
address chronic pain syndromes in women.
Use all mechanisms, including program
announcements, to study all facets of 1999 1996
pediatric CFS.
Address care needs, including the education
of providers in assessment, diagnosis and
treatment, case management, and 1999
rehabilitative efforts.
Establish chronic fatigue assessment and
treatment centers. 1999 1999b
aWorkshop.
bRecompeted.
External Review Recommendations to CDC and NIH
CDC's 1996 peer review, conducted by four scientists and two patient
advocates, noted that considerable progress had been made, specifically
outlining some strengths of the CFS program. The review team recognized
CDC's critical leadership role in the development of a case definition, the
valuable studies the agency had conducted on the rate of recovery from CFS,
and the agency's effort to study retroviral agents as a cause of CFS. The
report also included several recommendations: four general recommendations,
nine recommendations related to work conducted up to that time, three
recommendations related to proposed future studies, and two recommendations
related to possible additional research areas. For the most part, CDC has
undertaken activities in response to these recommendations. (See table 9.)
(Continued From Previous Page)
Recommendation CDC response
General recommendations
CDC's CFS team should enhance its
communications and collaboration with
NIH; NIH should regularly inform CDC
about ongoing progress and the results
of both its intramural and its
extramural research programs on CFS, CDC and NIH regularly provide
and CDC should regularly inform NIH updates to members of CFSCC and
about ongoing progress and the results attendees at that meeting regarding
of its ongoing studies. It appears their respective CFS programs.
that HHS' CFS Coordinating Committee
(CFSCC) concentrates primarily on
discussing the intramural research
programs at NIH and CDC.
Subsequent to this 1996 review,
CDC's CFS program should be regularly CDC's CFS program was reviewed in
reviewed by an external review group. 1999--the most recent external peer
review.
Provided the Viral Exanthems and
Herpesvirus Branch can develop The Viral Exanthems and Herpesvirus
additional expertise in the fields of Branch is developing expertise in
neuroendocrinology and neuroendocrinology and
neuropsychology, the placement of the neuropsychology through agreements
CFS program within that branch with Emory University.
continues to be appropriate.
CDC's CFS program should continue its
ongoing active dialogue with patient Meeting held at CDC in October
advocacy groups. 1999.
Recommendations related to program accomplishments to date
Statistical techniques, such as
cluster analysis and discriminant
function analysis, should be used to
assess the robustness of findings
related to case definition, and these Standard operating procedure.
same statistical techniques (including
factor analysis) should be applied to
other data sets as they emerge.
Investigations of potential clusters Program begins investigations of
of cases should begin as early as reported clusters as early as
possible after the onset of the possible. Emphasis in both cluster
putative outbreak to ensure the investigations and population
highest likelihood of identifying an studies is to detect and study
etiologic agent. incident CFS cases.
CDC should write a formal assessment
of the reasons for the considerable
differences in the observed prevalence Done in discussion of newest
rates from different studies, besides prevalence manuscript to be
differences in the completeness of the submitted for publication.
case ascertainment techniques across
the studies.
CDC should comment on the possible
biological implications of some of the
differences in prevalence it has Done in discussions of all
observed in different age, gender, and appropriate manuscripts.
socioeconomic groups.
Future studies should focus on
prevalence in children and geriatric
populations. Widely repeated anecdotal --Wichita surveillance includes all
evidence indicates that teachers, residents 2 years and older.
airline workers, and health care
workers may be differently affected. --The National Survey (planned for
(To some extent, such possible fall 2000) will give special
occupational associations have been emphasis to children.
evaluated already in the San Francisco
study, but it is not clear whether the --The National Survey will collect
sample size of this cross-sectional detailed information on possible
observational study allowed confident occupational associations with CFS.
conclusions.)
--CDC's most recent study of the
possible associations between CFS
CDC should continue some studies of and human herpesvirus 6 and 7 found
the possible role of human herpesvirus no association.
6 in CFS. The group strongly supports
further study of Borna disease virus. --CDC supported additional studies
CDC should also study the relationship of Borna disease virus, which found
of other known or newly-discovered no association with CFS.
microorganisms that could, on the
basis of their association with other --The Viral Exanthems and
similar illnesses or their tissue Herpesvirus Branch is developing
tropism, be potential triggering expertise in identification and
agents or cofactors for CFS. characterization of novel
infectious agents possibly
associated with CFS.
A regular formal process should be
instituted for reviewing and updating Standard operating procedure for
information for the public. In CDC programs. Program does not have
particular, these updates should resources to maintain and
reflect all published research, disseminate data on all published
whether conducted at CDC or elsewhere. CFS research.
--The web site now includes a
CDC's Internet web site should include summary of all new CDC work on CFS.
a written summary of all programs and
all work on CFS currently under way at --Printed copies of information are
CDC. Printed copies of the information available to those without Internet
should be available to those who do access. CDC operates a CFS voice
not have access to the Internet. The information system that offers the
web site might also contain a "Hot option of receiving printed
Topic" button that provides brief, materials. CDC also provides such
timely statements about CFS-related information in response to written
issues that have been highly visible queries.
in the media.
--The web site contains a Hot
Topics button.
Each public document about CFS and
each public presentation and media
interview about CFS should state NCID no longer uses this
clearly and prominently that CFS is a classification.
"priority one emerging illness."
Recommendations related to proposed future studies
--Approximately 8,000 subjects who
Some follow-up beyond a 1-year review completed detailed interviews
in Wichita should be planned with at during the initial survey have been
least a sample of the cases (and followed for 3 years. In addition
noncases) identified during the to monitoring the clinical courses
initial year. The study should attempt of the disease, this measures
to assess the level of incidence of CFS.
debility/functional status in this
population. The study should also --A manuscript describing
follow a sample of patients who report functional status at baseline is in
debilitating chronic fatigue but who preparation. Following the third
do not fully meet CDC's case year of follow-up, analyses will
definition of CFS. explore functional status over
time.
--Program determined after review
that this technique was not the
The representational difference most appropriate method and is
analysis technique should be used not using other strategies.
only with peripheral mononuclear cells
but also with tissue specimens and --At present, only peripheral blood
cerebrospinal fluid, when possible. cells can be collected from
subjects enrolled in
population-based studies.
Studies of stress and herpes simplex
virus 1 reactivation should not be Herpes simplex virus 1 reactivation
supported. protocol was stopped.
Recommendations related to possible additional research areas
CDC should develop some collaborations Neuroendocrinologist should be on
with neuroendocrinologists to study staff (through agreement with
the hypothalamic-pituitary axis. Emory) by September 2000.
CDC could provide an international
service by offering to create a brain
bank of specimens available for study, CDC will convene a meeting in fall
including other tissue specimens from 2000 to initiate this process.
these same patients, when possible.
Source: Recommendations from "External Peer Review of the Chronic Fatigue
Syndrome Research Program," August 1996. CDC responses reported to GAO.
Subsequent to the 1996 review, CDC underwent a 1999 peer review and a review
of the Board of Scientific Counselors. These two concurrent reviews had a
consistent message: CDC should look for more opportunities to collaborate.
Specifically, the reviews suggested that NIH researchers work with some of
the tissue samples obtained by CDC from the Wichita study. The peer review
also suggested that there be more professional education efforts. CDC has
many activities planned to address these recommendations (see table 10).
(Continued From Previous Page)
Recommendations CDC response
General recommendations
Broaden collaborations. Collaborations vary depending on
program at the time.
Broaden communication with Council of
State and Territorial Epidemiologists, In process.
advocates.
Standard operating procedure,
Broaden availability of patients and depending on program strategy and
specimens to scientific community. priorities and the quality of
proposals.
Recommendations related to surveillance
Continue Wichita cohort beyond 3 years. Clinical cohort time frame
extended.
A manuscript is being drafted, and
Study quality of life, economic burden, CDC is hiring a medical research
patient management, long-term care, and officer and conducting clinical
behavioral and functional sequelae. studies. CDC also plans to conduct
a national survey.
Explore CFS in families and A manuscript is being drafted, and
occupations. CDC plans to conduct a national
survey.
CDC is welcoming a pediatrician to
Place more emphasis on adolescents. complete a sabbatical year at CDC;
adolescents will be studied in the
national survey.
Use the modified case definition in
future studies. Standard operating procedure.
Recommendations related to case definition
Consider revising case definition. A workshop was conducted in May
2000 to consider this topic.
Use factor analysis on other databases. In process; planned as part of the
May 2000 workshop.
Measure chronic unwellness in the Survey will be designed to capture
national survey. such data.
Use factor scores (chronic unwellness)
to better weight symptoms and measure In process and part of the
severity. national survey.
Recommendations related to clinical
studies
Recruit a medical research officer. In process.
Convene a review group for endocrine
studies. In process.
Design protocols for neuropsychological Exploring this with Emory
studies combined with brain imaging. University.
Recommendations related to molecular epidemiology
Improve balance of gene expression
analysis program. In process.
Was part of the April 2000 Banbury
Conference, Strategies for
Develop a program to search for novel Identification and
uncharacterized infectious agents. Characterization of Unknown
Pathogens , which CDC co-organized
and cosponsored.
Recognize CFS as a contagious disease Clusters are examined on request,
that occurs in clusters. but CFS does not appear to be
contagious.
Assess risk of transfusion A statement regarding risk has
transmission. been released, and CDC continues
to monitor.
There is no evidence from CDC's
Broaden investigations to consider case control studies to support
environmental exposures/toxicology. this, but the agency continues to
monitor.
Recommendations related to education (focus on health care providers
should continue)
Maintain web page. Done.
Develop continuing medical education In process with HHS' Health
materials. Resources and Services
Administration.
Develop national CFS information CDC maintains a web page,
campaign. publishes journal articles, and
provides other information.
React to CFS articles in reviewed Standard operating procedure, when
journals and in popular press. appropriate.
Explore CFS education in schools and
establish liaison with the Department Will follow up, as appropriate.
of Education.
Source: Recommendations from CDC. CDC responses reported to GAO.
NIAID's National Advisory Allergy and Infectious Diseases Council meets
about three times a year and occasionally has discussed NIH's CFS program.
In conjunction with those discussions, the council has sometimes made
recommendations to that program. In February 1993, the council advocated
that NIH support specific studies suggested by findings from case
demographics. At its February/March 1994 meeting, the council concurred with
the need and desirability of continuing and expanding the CFS Cooperative
Research Centers program and reapproved the centers then and again in
September 1997. In September 1995, the Division of Microbiology and
Infectious Diseases subcommittee of the council more formally assessed the
CFS program and determined that NIAID should retain overall leadership of
NIH's CFS efforts but that a multidisciplinary research approach should also
continue, involving other institutes where appropriate. At the next council
meeting, in May 1996, the division asked for and obtained approval of a
program announcement on CFS, supported by eight institutes and offices. The
subcommittee noted that the initiative was responsive to its recommendation
to both explore new hypotheses of causes and disease development and to
involve other NIH entities in the CFS research effort. The subcommittee also
had a number of specific scientific suggestions. The areas of study that
were recommended included consideration of multiple disease causes, studies
of patients with shorter duration of illness, longitudinal studies of immune
markers correlated with clinical findings, information about factors
predictive of recovery and recovery rates, the use of tissue samples to test
theories involving certain cell alterations, issues related to pregnancy,
and epidemiological research into CFS in children and adolescents. NIH has
conducted investigations in all but two of these areas (studies of patients
with shorter duration of illness and issues related to pregnancy).
NIH also has an internal coordinating committee for CFS comprised of
representatives from all relevant and interested institutes within the
agency. While this might have been intended initially to serve as a forum
for intraagency communication, it has instead, according to agency
officials, more recently served as a way of providing information for use at
the meetings of HHS' CFSCC. Further, attendance at the meetings has been
optional, and agency officials reported that representatives from those
institutes that have small programs with only one or two grants rarely
attend.
NIH Expenditures on CFS Research, by Institute and Center
Fiscal year NCI NCRRa NHLBI NIAID NIAMSa NICHDa NIMHb NINDSa Totalc
1987 $0 $0 $0 $782 $0 $0 $0 $0 $782
1988 0 0 0 988 0 0 0 0 988
1989 0 4 0 1,472 0 0 0 0 1,476
1990 0 30 0 1,793 0 0 0 0 1,823
1991 0 25 0 2,710 0 0 112 15 2,861
1992 0 86 0 2,978 0 0 417 11 3,492
1993 550 38 0 3,841 0 0 1,311 6 5,746
1994 555 56 0 4,226 218 10 1,107 4 6,175
1995 560 103 0 5,252 231 0 1,226 1 7,372
1996 0 249 0 4,984 0 0 1,341 0 6,574
1997 0 222 0 4,966 0 0 1,491 0 6,678
1998 0 134 819 4,233 176 20 1,406 0 6,787
1999 0 138 794 4,434 209 0 1,156 161 6,892
Note: Dollars in thousands.
aFunding for institutes' and centers' projects was below NIH threshold for
disease reporting of $250,000. Because of our review, institutes and centers
were asked to more carefully examine their CFS project funding.
Nevertheless, there may be a slight underreporting of CFS funding.
bNIMH reported total funding for a CFS center project, consistent with its
policy to report entire projects. Following additional review, NIH
determined that only a portion of the project was related to CFS.
cDue to rounding, figures in total column may not be the sum of institutes'
and centers' yearly expenditures.
NIH Activities in Support of CFS Research
NIH has issued four program announcements to stimulate research on CFS. The
first, a program announcement initiated by NIAID in 1987, targeted studies
in the epidemiology of CFS and chronic Epstein-Barr virus infection to
advance understanding of the prevalence, causes, and natural history of
these syndromes.32 In 1992, NIAID initiated a program announcement that
called for applications to explore biologically rational hypotheses
concerning exercise-induced fatigue and/or disease origin and development in
CFS patients. In 1994, NIH issued its first joint program announcement--with
NIAID, NIAMS, and NIMH--calling for studies on the causes, natural history,
and origin and development of CFS. This announcement listed 10 different
areas that merited further study, including low levels of cortisol, sleep
disturbance, demographic risk factors, and increased frequency of
psychiatric diagnoses in CFS patients. The most recent program announcement
was issued in 1996 and involved eight different units within NIH. This
program announcement was designed to support studies of CFS' functional
effects on the body, ideally addressing new hypotheses and research gaps, or
small studies exploring new ideas. This program announcement listed 23 areas
needing additional research.33
NIH officials told us they established a CFS Special Emphasis Panel for the
review of CFS grant applications for a number of reasons, including
demonstrating the agency's commitment to CFS research, because CFS is little
understood and because so few applications for CFS were being received. The
panels were designed to help facilitate consideration and scoring of CFS
grant applications that might otherwise not receive scores favorable enough
to be funded if reviewed by a standing study section. Members are selected
for a special emphasis panel after grant applications are received so that
those with appropriate expertise are appointed to serve as reviewers. Like
all review panels, members of the CFS Special Emphasis Panel are external
researchers, not employees of NIH. An NIH official told us that most
applications that have gone to the CFS Special Emphasis Panel have received
better scores than they would have if they had gone to a standing study
section. At the National Advisory Allergy and Infectious Diseases Council
meeting in February 1993, the chief of the Virology Branch commented that
the application review process had improved significantly since the
establishment of a special emphasis panel for CFS. To date, of the
applications reviewed by the CFS Special Emphasis Panel, a total of 30
extramural grants (R01 grants, or research projects) have been funded. (See
app. IV.)
The CFS Special Emphasis Panel was designed to help improve the chances of
CFS grants getting funded. During fiscal years 1988 through 1999, the
funding rate for CFS was 24.32 percent versus 28.31 percent for all grants
across the same institutes that fund CFS research. It is plausible that the
quality of CFS applications has been inferior to the quality of those in
other areas, accounting for the lower rates. It is also plausible that this
rate of funding is indeed higher than it would have been had the
applications been reviewed by standing panels.
The agency has used an additional approach for facilitating the funding of
CFS research. NIH has a process for all areas of research, called "selective
payment," designed to provide funding to a small number of applications that
are programmatically important but not rated favorably enough to receive
funding. From 1992 through 1996, six CFS applications were funded--all by
NIAID--through this process. NIH's description of the selective payment
process states that it is designed to support applications that received
scores just beyond the funding cut-off; however, the CFS applications funded
through this process were, in fact, ranked quite poorly.34 NIAID appears to
have made extra efforts to fund some CFS research.
In addition to these efforts, NIH has issued three requests for applications
for CFS Cooperative Research Centers since 1991. The centers are designed to
augment the existing grant program and to provide a sustained
multidisciplinary approach to CFS research. The intent is to advance the
field by bridging the basic science and clinical research arenas and
facilitating confirmatory testing and follow-up of new hypotheses and
observations. The purpose of the initial request for applications, issued in
1991, was to stimulate the establishment of centers of CFS research
excellence in which coordinated projects in the fields of immunology,
virology, medicine, and clinical epidemiology could be pursued. These awards
were for a period of up to 4 years, with funds set aside for this purpose.
NIAID funded three centers with the fiscal year 1991 request for
applications, two with the second request in fiscal year 1995, and three
with the final request in fiscal year 1999. Under the last request for
applications, funds had been set aside for only two centers. However, few
CFS grant applications had been funded that year, and we were told that,
because the agency wanted to spend money on CFS research, the extra grant
funds were used to support a third center.
NIH's institutes and centers award grants to nonprofit and for-profit
organizations; institutions of higher education; hospitals; research
foundations; governments and their agencies; and, occasionally, individuals.
Applications are usually initiated by the principal investigator, signed
also by an authorized official of the applicant institution, and these are
received by NIH's Center for Scientific Review. Approximately 37,000 grant
applications are processed each year. Applications are ordinarily
unsolicited, but NIH may encourage the submission of grant applications on
particular topics through the use of one of two special devices: program
announcements--which describe continuing, new, or expanded program
interests--and requests for applications, which invite applications in a
well-defined scientific area and for which specific funds have been
earmarked and a special review process has been designed.
Within the Center for Scientific Review, all applications that are competing
for funds are assigned to a specific institute or center and to an
integrated review group. The institute or center chosen is the one that may
eventually have the opportunity to fund the research. The review group
chosen is the one that would be most appropriate for assessing the
scientific merit of the research grant application.
An integrated review group is a chartered organization divided into study
sections, each of which is composed of 12 to 20 mostly nonfederal scientists
who are selected for their competence and generally serve 4-year terms.
These members are sent copies of the relevant applications about 6 weeks
before the study section's scheduled meeting; for each application, specific
members are chosen to provide written reviews or to act as discussants. A
special emphasis panel operates like a study section in that it peer reviews
applications, but it is formed on an ad hoc basis, and it reviews
applications on only a relatively specific topic.
One week before a study section meets, the Scientific Review Administrator
from the Center for Scientific Review solicits from all members a list of
applications believed not to rank in the top half for scientific merit. The
individual lists are compared and those on all lists are not discussed at
the meeting. At a meeting of the study section, the review administrator and
a chairperson from the study section jointly conduct the peer review, which
usually lasts 2 days. Observers, such as program staff from the relevant
institutes and centers may attend but do not participate in the discussions.
Reviewers and discussants assigned to an application provide their
evaluations. Then, after a general discussion, members mark their priority
scores privately for each application. Average priority scores and
percentiles are eventually generated for each one as summary outcomes of
this peer review process. The review instructions are the same for standing
study sections and special emphasis panels.
Applicants are provided with detailed feedback from the study section
meeting in about 6 to 8 weeks, but final decisions about awards depend on
further steps centering around a second level of review by the institute's
advisory council. For NIAID, the National Advisory Allergy and Infectious
Diseases Council conducts this second review. This council and the
equivalent councils or boards in other institutes and centers are
responsible, by law, for the final external review of all grant applications
recommended for further consideration. Its members represent health,
science, and the public. The second level of review is designed to evaluate
applications in relation to the needs of the institute or center and the
priorities of its director. The council may concur with the review group (or
special emphasis panel) recommendations or it may vote to change the
first-level review recommendations via several different mechanisms. This
can include applications selected for funding under selective payment.
Selective payment requires that an institute or center reserve a portion of
extramural research funds for applications that meet programmatic needs but
are scored at the margin of the pay cut-off. Generally, studies are
identified for selective payment by the institute or center director and are
evaluated by the unit's advisory council.
Comments From the Department of Health and Human Services
1. Our draft report acknowledged that agency officials told us that
communication between agency scientists occurs on an informal basis and that
much of the research funded by the agencies is extramural in nature.
Moreover, we did not question whether CDC or NIH officials communicate with
each other. Rather, we reported that we found no evidence of collective
research resulting from this informal communication.
2. We noted in the draft report a number of misperceptions that patient
advocates seem to have about the work at NIH. For example, regarding patient
advocates' concern about the lack of research on mycoplasma, we note that
the agency has not received grant applications on mycoplasma; therefore, NIH
is unable to fund such work. We also note that the agency has not
disproportionately funded research on issues related to CFS and mental
health.
3. We noted in multiple places in the draft report that only one planned
study--on CFS in adolescents--was not initiated by CDC because of
insufficient funds and that the agency later determined the study would be
infeasible. However, CDC now has activities planned in at least five areas,
using $12.9 million the agency is providing to replace funds previously
redirected. This suggests that had those funds been available at the time
they were budgeted and had adequate planning occurred, these activities
could have been initiated earlier.
4. There is no objective way for either NIH or us to know how the use of a
special emphasis panel to review grant applications has influenced the
scoring and funding of those applications. We have added to our report that
agency officials believe that review by the special emphasis panel improves
the chances that a grant application will get a fundable score.
5. The state of the science meeting was originally discussed during the
April 1999 meeting of CFSCC and was planned to run in conjunction with the
fall meeting of the committee. According to documents we received, meetings
began in August 1999 between agency officials and a patient advocate member
of CFSCC around planning the state of the science meeting. In October 1999,
members of CFSCC were informed by the executive secretary of the committee
that the state of the science meeting would not take place at the same time
as the fall committee meeting because many of those who were invited were
unable to attend on the dates selected. The October communication also
indicated that members of CFSCC would be informed as soon as a new date was
selected, presumably so they could plan to attend the meeting. While the
meeting was briefly discussed at CFSCC's November 1999 meeting, the draft
minutes of that meeting do not make clear that the meeting would no longer
be public. It was not until December 1999 that an agency official reported
to a CFS professional association that the meeting would not be open to the
public. It was some time later that CFSCC members were invited to observe
the meeting. However, they were not consulted in the agency's decision to
shift the focus of the meeting from informing CFSCC on the current state of
the science to an NIH CFS consultation. The draft report noted that CFSCC
members raised concerns about the participants in general, as well as a
number of specific participants invited to attend.
(101862)
Table 1: U.S. Studies of CFS Prevalence Based on Clinical
Evaluation of Samples of Local Populations 32
Table 2: NIH Disposition of Projects Identified by CRISP From 1997 Through
1999 Not Included in NIH's List 47
Table 3: NIH-Funded R01 (Research Project) Grants Related to CFS 48
Table 4: NIH-Funded Intramural Research Projects Related to CFS 49
Table 5: NIH-Funded Grants and Projects Not Including R01
(Research Project) Grants and Intramural Projects Related
to CFS 50
Table 6: NIAID Cooperative Research Center Projects Related to
CFS 52
Table 7: Congressionally Requested CFS Activities for CDC 54
Table 8: Congressionally Requested CFS Activities for NIH 57
Table 9: Recommendations From CDC's 1996 Peer Review and
Agency Response 59
Table 10: Recommendations From CDC's 1999 Peer Review, Board of Scientific
Counselor Review, and Meeting With Patient
Advocates, and Agency Response 61
Figure 1: CDC Funding, Fiscal Years 1988 Through 1999 14
Figure 2: NIH Expenditures, Fiscal Years 1988 Through 1999 16
Figure 3: Proportion of CFS Funds Retained at Each Level of
CDC, Fiscal Years 1998 Through 1999 19
Figure 4: CDC Publications 39
1. The Congress did not make a line item appropriation to the CFS program.
Rather, the appropriations committees expressed their funding expectations
for the CFS program in reports that accompanied the annual "lump sum"
appropriation to CDC. See, for example, H.R. Rep. No. 103-156, at 44 (1994);
S. Rep. No. 103-143, at 69 (1994); and H.R. Conf. Rep. No. 105-825, at 1270
(1998). Because the Congress did not use a line item appropriation to fund
the CFS program, the CDC director had latitude in determining whether funds
would be allocated in strict accordance with the CFS program funding
guidance expressed by the Congress.
2. These have included pharmacological therapies, such as medications to
improve sleep or relieve pain, and nonpharmacological therapies, such as
acupuncture, chiropractic manipulation, massage, and yoga. Certain
psychotherapies, such as cognitive behavior therapy, have also been used in
efforts to help patients cope and alleviate some of the symptoms associated
with CFS. In addition, some consider that modest regular exercise to avoid
deconditioning is important.
3. The four additional institutes and centers are the National Institute of
Environmental Health Sciences, the National Institute of Nursing Research,
the National Institute of Diabetes and Digestive and Kidney Diseases, and
the Office on Research on Women's Health.
4. Federal agencies other than CDC and NIH have the following roles related
to CFS: new CFS-related products or advertising require review by FDA; the
Health Resources and Services Administration generally translates research
findings into practice and addresses issues related to the training of
health professionals; and the Social Security Administration tracks medicine
and science behind disorders like CFS so that their policies reflect the
clinical world, especially related to rulings on CFS disability claims.
5. See H.R. Rep. No. 100-256, at 50 (1988); and S. Rep. No. 100-189, at 69
and 110 (1988).
6. For CDC, we refer only to funds budgeted for CFS research because the HHS
Inspector General review of the CFS program at CDC found that CDC had been
unable to clearly identify funds actually spent on CFS.
7. The staffing levels represent only those who work directly for CDC on
CFS, although much of CDC's work on CFS is conducted extramurally, as is
most of CDC work in general.
8. For NIH, we refer to expenditures--that is, funds that were spent on
grants (extramural), projects (intramural), and cooperative agreements.
9. The staffing levels represent only those scientists who work directly for
NIH on CFS, although much of NIH's work on CFS is conducted extramurally, as
is most of NIH work in general.
10. According to agency officials, other staff--such as the division
director, branch chief, committee management staff, and budget staff--also
devote time to work on CFS at NIH.
11. Agency-level indirect costs pay for, among other things, all offices of
program support, three facilities offices, design, construction,
maintenance, a financial management office, human resources management,
information resources management, utilities, a procurement and grants
office, a management analysis and services office, and mail. Center-level
indirect costs are used to support the Office of the Director and the
Scientific Resources Program. The Scientific Resources Program covers lab
program services for all of the divisions and branches, including glassware,
animal work, infrastructure, chemicals, and the making of reagents. The
division portion of indirect costs has been used for, among other things,
support of maintenance agreements on all equipment, telephones, hardware
support of computers, and equipment for the Office of the Director (such as
facsimiles and photocopiers).
12. The agency continues to develop its procedures for calculating indirect
costs and expects to have them finalized by fiscal year 2001. Each center is
also developing procedures for calculating indirect costs, though these are
not expected to be implemented until after the agency procedures are
implemented. Accordingly, the National Center for Infectious Diseases has
requested an external review of its indirect cost methodology. Further,
divisions will not begin similar work until after the centers have
implemented their procedures.
13. Officials have said that CDC has recently improved this process. For
example, agency officials reported that tentative ceilings were provided to
the center within 30 calendar days of passage of its appropriations bill for
fiscal year 1999 and within 17 calendar days for fiscal year 2000.
14. Prior to fiscal year 1997, the Viral Exanthems and Herpesvirus Branch
did not have an administrative officer, and budget allocations to the branch
prior to that time did not indicate a date for the allocation.
15. CDC was unable to provide allocation memorandums for any fiscal years
prior to fiscal year 1994 or for fiscal year 1995.
16. CDC has since initiated the hiring process of a neuroendocrinologist. We
were told that the lengthy delay in hiring was due to a lack of an
appropriate candidate, not a lack of funds. The adolescent study was later
found not to be feasible for methodological reasons.
17. The percentile rankings of all CFS applications funded under the
selective payment program ranged from 53.7 to 75, well above what would be
expected with just over 28 percent of the applications being funded overall.
A high percentile ranking is assigned to applications with poor scores, and
a low percentile ranking is assigned to those with good scores.
18. NIAID intramural scientists collaborated with other NIH scientists on
studies of the neuroendocrine system, seasonal variations in CFS patients,
diagnosis and treatment of CFS, the measurement of fatigue, the
characteristics of patients with CFS, memory function, and the relationships
between CFS and induced episodes of illness and of fatigue. NIAID intramural
scientists also collaborated with extramural researchers on a study of a
therapy for neurally mediated hypotension. Neurally mediated hypotension is
a disturbance in the autonomic nervous system's regulation of blood pressure
and pulse, characterized by abnormally low blood pressure under certain
circumstances.
19. Among the concerns patient advocates raised over the proposed list of
participants are the following: (1) the list did not include any broad-based
CFS experts, such as one of the past or present NIH CFS Cooperative Research
Center directors; (2) the list did not include anyone who regularly saw CFS
patients to draw on clinical experience; (3) two participants were included
who are known for promoting psychiatric approaches to CFS and cognitive
behavioral therapy research; and (4) an NIH scientist was asked to provide
an overview of CFS research for the meeting, despite the scientist's no
longer being actively involved in CFS research.
20. CFSCC's five goals are (1) provide advice to the Secretary of HHS and
others to ensure interagency coordination and communication regarding CFS
research and other related issues, (2) develop complementary research
programs that minimize overlap, (3) facilitate increased department and
agency awareness of CFS research and educational needs, (4) identify
collaborative and coordination opportunities in research and education, and
(5) develop informed responses to constituency groups regarding agency
efforts and progress.
21. A product used to treat a rare disease affecting fewer than 200,000
Americans may be designated as an orphan drug and thereby qualifies the
manufacturer for exclusive marketing for 7 years and tax incentives.
22. G. P. Holmes and others, "Chronic Fatigue Syndrome: A Working Case
Definition," Annals of Internal Medicine , Vol. 108 (1988), pp. 387-9.
23. W. J. Gunn and others, "Epidemiology of Chronic Fatigue Syndrome: The
Centers for Disease Control Study," Ciba Foundation Symposium , Vol. 173
(1993), pp. 83-101.
24. M. Reyes and others, "Surveillance for Chronic Fatigue Syndrome--Four
U.S. Cities, September 1989 Through August 1993," Morbidity and Mortality
Weekly Report , Vol. 46
(SS-2) (Feb. 21, 1997), p. 1-13.
25. M. Reyes and others, "Random-Digit-Dialing Survey of Fatiguing Illness
in Sedgwick County, Kansas (Wichita)." Paper presented at the American
Association for Chronic Fatigue Syndrome International Research Conference
(Boston, Mass., Oct. 10, 1998).
26. W. Reeves at meeting of Chronic Fatigue Syndrome Coordinating Committee
(Washington, D.C., Apr. 22, 1999).
27. L. A. Jason and others, "A Community-Based Study of Chronic Fatigue
Syndrome," Archives of Internal Medicine , Vol. 159 (1999), pp. 2129-37.
28. Epstein-Barr virus has been implicated in a number of medical
conditions, including mononucleosis, and the similarity of CFS to chronic
mononucleosis led to the hypothesis that CFS was due to chronic Epstein-Barr
infection.
29. Causes that have been studied include, for example, human retroviruses,
human herpesvirus 6, enteroviruses, rubella, Borna disease viruses, Candida
albicans, and mycoplasma.
30. For example, CDC has looked at the association of CFS with chronic
enteroviral infections; associated viral infections and immunological
abnormalities; viruses like human T-cell lymphotropic virus type II;
retroviruses; Borna disease virus; physical, behavioral, and psychological
risk factors; strain differences in common viral infections; and
neuroendocrine function. Laboratory work has involved immune function
assays, including lymphocyte markers, cytokines, natural killer cell
dysfunction, serum Ig levels, complement levels, and immune complexes. CDC
also cultured specimens in attempts to isolate herpesvirus 6 and 7.
31. NIH funded a number of studies comparing CFS patients and healthy
controls with respect to potential laboratory markers and risk factors,
including sleep patterns and various neurologic, virologic, and immunologic
features. Some additional etiological hypotheses that were tested include
those implicating orthostatic intolerance, other aspects of cardiac
regulation, hypothalamic dysfunction, autoantibody responses, allergies, and
the dysregulation of specific antiviral pathways.
32. At the time, some experts believed there might be a relationship between
CFS and Epstein-Barr virus.
33. These areas included overlapping symptomatology with neurally mediated
hypotension, the role of cardiovascular regulatory centers, role of
neuroendocrine and neuroimmune functions, hormonal effects, and the role of
environmental agents.
34. The percentile rankings of all CFS applications funded under the
selective payment program ranged from 53.7 to 75--well above what would be
expected with just over 28 percent of the applications being funded overall.
A high percentile ranking is assigned to applications with poor scores and a
low percentile ranking is assigned to those with good scores.
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