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United States General Accounting Office
GAO     June 2000

Report to the Honorable Harry Reid, U. S. Senate

CHRONIC FATIGUE SYNDROME

CDC and NIH Research Activities Are Diverse, but Agency Coordination Is Limited

GAO/ HEHS-00-98

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Contents
Letter 3
Appendixes 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

Tabl es 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 3
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Contents
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Figures 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

Abbreviations
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 4
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United States General Accounting Office Washington, D. C. 20548
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Health, Education, and Human Services
B-283171 Letter
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 5
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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.

Results in Brief 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

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. 6
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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.

Background 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 7
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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

Federal CFS Research Through CDCand NIH 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.)

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. 8
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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.

Role of CFSCC 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

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. 9
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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.

CDC and NIH Research Activities Are Diverse 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.

CDC and NIH Conduct a Broad Range of CFS
Activities Consistent With 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

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. 10
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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 11
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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.

CDC and NIH Initiated Most Activities Requested by the
Congress

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.)

5 See H. R. Rep. No. 100-256, at 50 (1988); and S. Rep. No. 100-189, at 69 and 110 (1988). 12
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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.

CDC and NIH Initiated Most CFS-Related Activities in
the Agencies' 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. 13
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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.)

CDC's Funding Practices Have
Impeded CFS Research in Contrast to 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. 14
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CDC and NIH Resources for CFS Research Have
Increased, but These 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.

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. 15
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Figure 1: CDC Funding, Fiscal Years 1988 Through 1999
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.

0
1000
2000
3000
4000
5000
6000
7000
8000
9000

1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988
Actual Dollars

Adjusted for Constant Fiscal Year 1999 Dollars
Funding (Dollars in Thousands)

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. 16
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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.

8 For NIH, we refer to expenditures— that is, funds that were spent on grants (extramural),
projects (intramural), and cooperative agreements. 17
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Figure 2: NIH Expenditures, Fiscal Years 1988 Through 1999
0
1000
2000
3000
4000
5000
6000
7000
8000
9000

1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987
Actual Dollars

Adjusted for Constant Fiscal Year 1999 Dollars
Expenditures (Dollars in Thousands)
18
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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

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. 19
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CDC's Processes and Timing for Allocating Funds Has
Impeded CFS 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.

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. 20
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Figure 3: Proportion of CFS Funds Retained at Each Level of CDC, Fiscal Years 1998
Through 1999

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.

19%
Centers for Disease
Control and Prevention

13%
National Center for
Infectious Diseases

12%
Division of Viral and
Rickettsial Diseases

56%
Viral Exanthems and
Herpesvirus Branch 21
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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.

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. 22
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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.

NIH Has Used a Number of Mechanisms to Facilitate
Support of CFS 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

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. 23
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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.

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. 24
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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.

Limited Coordination Through Agency
Efforts or CFSCC

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.

CDC and NIH Coordination and Involvement of Patient
Advocates and 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.

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. 25
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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. 26
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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

CFSCC Has Provided a Forum for Communication
but Has Not Ensured a 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

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. 27
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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, 28
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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.

Conclusions 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 29
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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.

Agency Comments 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. 30
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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 31
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Appendix I
Appendi xes Background on Chronic Fatigue Syndrome Appendi xI

CFS Case Definition 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." 1 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

1 G. P. Holmes and others, "Chronic Fatigue Syndrome: A Working Case Definition," Annals
of Internal Medicine, Vol. 108 (1988), pp. 387-9. 32
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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.

Estimates of CFS Prevalence 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 minimumprevalence rates,
over a 2-year period, ranging across cities from 2. 0 to 7. 3 per 100, 000. 2 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. 3 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. 4

2 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.

3 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.

4 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). 33
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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. 5 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. 6 The estimated rate for women was reported to be even
higher: 522 per 100,000.

Table 1: U. S. Studies of CFS Prevalence Based on Clinical Evaluation of Samples of Local Populations

a Adjusted for age, sex, and race, where indicated.
Research on Possible Causes of CFS 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. 7 Similarly, many known human infectious agents,
including other viruses and nonviral pathogens have been studied as
possible causes of CFS. 8 So far, none of the infectious agents studied have
been found to be significantly associated with CFS. It is possible, however,

5 W. Reeves at meeting of Chronic Fatigue Syndrome Coordinating Committee (Washington,
D. C., Apr. 22, 1999).

6 L. A. Jason and others, "A Community-Based Study of Chronic Fatigue Syndrome,"
Archives of Internal Medicine, Vol. 159 (1999), pp. 2129-37.

Study Method a Rates (per 100, 000) Estimated number of people with CFS in U. S. population
Gunn and others (1993), four cities 2-year prevalence 2.0-7.3 4, 000-14,000
Reyes and others (1997), four cities 4-year prevalence, adjusted 4. 0-8. 7 8, 000-17, 000
Reyes and others (1998), Wichita Prevalence, adjusted 183 363, 000
Reeves (1999), Wichita Prevalence, adjusted 238 471, 000
Jason and others (1999), Chicago Prevalence 422 836, 000

7 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.

8 Causes that have been studied include, for example, human retroviruses, human
herpesvirus 6, enteroviruses, rubella, Borna disease viruses, Candida albicans, and mycoplasma. 34
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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. 35
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Appendix II
Accounting Issues at CDC Appendi xII

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. 36
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° 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. 37
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Appendix II Accounting Issues at CDC
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° 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. 38
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Appendix III
CDC Research Efforts and Publications Appendi xI II

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 39
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Appendix III CDC Research Efforts and Publications
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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. 1 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.

1 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. 40
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Appendix III CDC Research Efforts and Publications
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Figure 4: CDC Publications
41
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Appendix III CDC Research Efforts and Publications
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42
42 Page 43 44
Appendix III CDC Research Efforts and Publications
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43
43 Page 44 45
Appendix III CDC Research Efforts and Publications
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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, 44
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Appendix III CDC Research Efforts and Publications
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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. 45
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Appendix IV
NIH Research Efforts and Grants Appendi xI V

NIH Research Efforts 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. 1 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.

1 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. 46
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Appendix IV NIH Research Efforts and Grants
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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.

NIH-Funded Grants and Projects Related to
CFS

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. 47
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Appendix IV NIH Research Efforts and Grants
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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). 48
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Appendix IV NIH Research Efforts and Grants
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Table 2: NIH Disposition of Projects Identified by CRISP From 1997 Through 1999 Not Included in NIH's List
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).

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 49
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Appendix IV NIH Research Efforts and Grants
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Table 3: NIH-Funded R01 (Research Project) Grants Related to CFS
Fiscal year( s) Institute Grant title Total funding in dollars
1987-1990 NIAID Definition of the Chronic Epstein-Barr Virus Syndrome $540, 220
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 Acute Viral Infection a 716, 106
1993-1997 NIAID Human JHK Virus b 769, 203
1993-1995 NIAID Exertion-Induced Cytokines in CFS b 536, 958
1993-1995, 1997-1999 NIAID Motor Control and Cytokines in CFS (later retitled Motor Control in CFS) b 970, 696

1993-1995 NIAID Exercise Intolerance in CFS 454, 121
1993-1999 NIMH Research Center on the Psychobiology of Ethnicity c 6,978, 751
1993 NIAID Virology Assessment of CFS Patients d 6,910
1993-1996 NIAID Antigens of Human Herpesvirus-6 521, 694
1994-1996 NIAID Virology and Immunology of CFS b 497, 473
1994-1996, 1998-1999 NIAID Mechanisms of Immunologically Mediated Fatigue 1, 008, 464

1995-1999 NIAID Estimating Rates of CFS in a Community Sample 2, 714, 041
1995 NCI Transforming Domain of Human Herpesvirus-6 That Transactivates HIV 1 207, 000
1995 NCI Epidemiologic Study of Pediatric HIV-Related Lymphomas 55, 000
1995 NCI Molecular Studies on Bovine Immunodeficiency Virus and Bovine Herpes Virus Interactions 21, 000

1996-1998 NIMH Cognitive Dysfunction in CFS 275, 836
1996-1999 NIAID Dysregulated 2-5A Synthetase/ RNase L/ PKR Pathways in CFS e 1,086, 909
1996-1998 NIAID A Trial of Fludrocortisone for CFS b 748, 132
1997-1999 NIAID Autoantibodies to Cellular Matrix Antigens in CFS 1, 063, 378
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 People with Chronic Fatigue 859, 156
1998-1999 NHLBI Investigation of Orthostatic Intolerance in CFS 639, 674
1998-1999 NIAMS HPA Axis Dysregulation in Fibromyalgia 385, 015
1999 NIMH Auditory Working Memory in CFS: A Functional Magnetic Resonance Imaging Study 135, 152

1999 NHLBI Muscle Blood Flow and CFS 114, 359
1999 NINDS Motor Learning in CFS: Implications for Neural Dysfunction 160, 665
Total funds $25,162, 062 50
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Appendix IV NIH Research Efforts and Grants
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a This 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.
b Grant 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.
d From 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.

e The first-year funding for this grant was under exploratory/ developmental grants.

Table 4: NIH-Funded Intramural Research Projects Related to CFS

Fiscal year( s) Institute Grant title Total funding in dollars
1987-1988 NIAID Study of Sporadic Neurasthenia Associated With Epstein-Barr Virus $928, 400
1989-1996 NIAID Chronic Epstein-Barr Virus Infection and CFS 6, 001, 482
1991-1995 NINDS Neuropsychological Investigations of Human Cognition and Mood State 30, 234
1991-1993, 1995 NIMH CNS Role in the Susceptibility to Inflammatory Illness 428, 000
1992-1993 NINDS Combined Clinical, Viral, and Immunological Studies of Neuromuscular Diseases 6,125

1993-1994 NCI Epidemiology Studies and Basic Research Related to CFS Outbreaks and Characterization of the Viruses Associated With CFS 399, 000
1993-1994 NCI Support for Physicians Treating CFS Patients by the National Physicians Advisory Group 706, 000
1993, 1995-1999 NIMH Neurobiology of Unipolar Depression 1, 033, 808
1994, 1998 NICHD Dose-Response Relationships for Single Doses of Recombinant Human Interleukin-6 in Normal Volunteers and in Patients With Disorders of the

Hypothalamic-Pituitary-Adrenal Axis
30, 000

1995 NCI Identification of Human Genetic Loci Which Influence Susceptibility to HIV 115, 000
1995 NCI Regulation of Viral and Cellular Gene Expression 30, 000
1995 NCI Genetic Variation in Infected Hemophiliacs Over Time 30, 000
1997-1998 NIAID Multidisciplinary Studies of CFS 1, 795, 181
1997-1999 NIAID Trial of Fludricortisone for Patients With CFS 524, 488
Total funds $12,057, 718 51
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Appendix IV NIH Research Efforts and Grants
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Table 5: NIH-Funded Grants and Projects Not Including R01 (Research Project) Grants and Intramural Projects Related to CFS
Fiscal year( s) Institute Grant title Total funding in dollars
1987-1996 NIAID Pathogenesis of Epstein-Barr Virus Infections $2, 896, 620
1989 NCRR Prevalence of CFS in Ambulatory Medicine 3, 949
1989 NCRR Immunologic and Virologic Studies of CFS 188
1990 NCRR Sleep and Cytokines in CFS 21, 178
1990 NCRR Involvement of a Human Retrovirus in CFS 8, 531
1990 NCRR Analysis of Clinical and Biological Characterization of CFS 350
1991 NCRR Psychology and Immunology of CFS and Other Disorders With Severe Fatigue 2, 609
1991 NCRR Acute Experience: Stress and Immune Function in CFS Patients 3, 447
1991-1992 NCRR Ampligen in Patients With CFS and Associated Encephalopathy 103, 584
1992-1993 NCRR Electroencephalogram Sleep in CFS 6, 170
1993-1996 NCRR Exertion Induced Cytokines in CFS 147, 883
1993, 1996 NIAID Coordinating Center for Clinical and Epidemiologic Studies in Infectious Diseases 21, 567

1993-1997 NIAID Social Processes and Somatization— The Course of CFS 625, 463
1993, 1995-1999 NCRR Phosphocreatine Recovery in Women With CFS 111, 802
1994-1995 NIAMS Cytotoxic T Lymphocyte Mediated Cutaneous Immunity to Melanoma 185, 399
1994-1995 NIAMS Molecular Basis of T-Cell Helper Function 92, 610
1994-1995 NIAMS Molecular Determinants of Epstein-Barr Virus Tropism 171, 203
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 Hematopoietic Malignancies 102, 000
1996 NCRR In Vitro Effects of Interleukin 2 on Activity of Natural Killer Cells in CFS 273
1996 NIAID Operations and Technical Support 444, 673
1996 NCRR Clinical Application of Deoxymyoglobin Technique: Peripheral Vascular Disease or CFS 28, 718

1996 NIAID 1996 Scientific and Clinical Meeting, CFS 2, 000
1996 NCRR Microbial Genomic Sequencing in Emerging Disease With Unknown Etiology: Kawasaki, CFS 121, 392

1997-1998 NCRR Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia 130, 814
1997 NCRR Comparative Study of Pathophysiologic Descriptors of CFS 1, 912
1997-1998 NCRR Trial of Fludrocortisone for CFS 25, 119
1997-1998 NCRR Regulation of Adrenal Function in Fibromyalgia 129, 609
1997 NCRR Immunoneuroendocrine Response to Tetanus Toxoid 19, 690
1998 NCRR Psychiatric Diagnosis and Biological Markers in Neuresthenia, CFS, and Depression 18, 516 52
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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 Neuroendocrinological Response 315
1999 NCRR Mechanisms of Rhinitis in CFS 47, 865
1999 NCRR Skeletal Muscle in Persian Gulf Veterans With CFS 21, 009
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 CFS 67, 827
Total funds $6, 029, 109

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Fiscal year( s) Institute Grant title Total funding in dollars 53
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Appendix IV NIH Research Efforts and Grants
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Table 6: NIAID Cooperative Research Center Projects Related to CFS
Fiscal year( s) Grant title Total funding in 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 Quantification of Fatigue 411, 666
1992-94 Developmental Research on CFS and Quantification of Fatigue 56, 248
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, Sleep Function 493, 145
1995-98 Immunology and Virology of CFS in Monozygotic Twins 662, 290
1995-98 Biological/ Psychosocial Factors: Post-Infectious Fatigue 490, 453
1995-98 Prognosis of CFS 525, 887
1999 Monozygotic Twins With CFS— Predisposition of Perception 269, 612
1999 Population Based Twin Study of CFS 202, 822
1999 Biostatistical and Data Management 140, 142
1999 Children of CFS Patients 140, 082 54
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Appendix IV NIH Research Efforts and Grants
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University of Miami (1999-present)
1999 Cognitive-Behavioral Stress Management Intervention for CFS 136, 299
1999 Effect of Stress and Cognitive-Behavioral Stress Management on Natural Killer Activity in CFS 61, 147
1999 Laboratory Assessment 153, 311
Total funds $14,399, 965

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Appendix V
Congressionally Requested CFS Activities for CDC and NIH Appendi xV

CDC Response to Congressional
Committee Requests for CFS Activities

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.

Table 7: Congressionally Requested CFS Activities for CDC
Activity requested Year( s) requested Year( s) started
Develop and implement a surveillance network. 1988 1988
Expand surveillance system to all states. 1988 a
Increase level of research support. 1988 1988 b
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 appropriate controls. 1989 1992

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 CFS. 1990 1990
Expand research on immunologic abnormalities. 1990 1992
Provide CFS information, outreach, conference, and training activities. 1991 1991
Refine CFS definition. 1991 1991 56
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a National survey planned for 2000.
b Funding levels show an increase since 1988.
c Meeting planned.
d Does not include pregnant women.
e Findings presented.
f CDC has found no evidence that CFS is transmissible.
g Data used as pilot of Wichita study.
h Etiology studies began in 1996; brain tissue repositories in 2000.
i Hiring in process.

Study the establishment of a CFS patient registry. 1991 2000 c
Develop recommendations to the U. S. biomedical community on standardized clinical data collection instruments and procedures for evaluating functional health status in CFS. 1991, 1992 1994

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 of the disease, and research on the

impact of CFS on health professionals.
1993 1994 d

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, and data related to CDC
responses to cluster outbreaks of CFS.
1993 1990 e

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 the basic epidemiology of CFS. 1995 1993

Support four studies on possible transmission routes, especially among health care workers, family members, and maternal transmission to unborn children. 1995, 1996 f
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 completed in San Francisco. 1996 1997 g

Consider implementing the review panel's recommendations, particularly in the areas of etiology studies and brain tissue repositories. 1997 1996, 2000 h
Enhance CFS laboratory studies and surveillance projects, including outreach to populations not previously recognized as being affected by CFS, especially minorities, children, and adolescents. 1998, 1999 1997
Encourage continuation and expansion of studies of adolescents and children. 1998 1993
Add a neuroendocrinologist to research group. 1998, 1999 1999 i
Initiate studies on rates of CFS among health care workers, family members of CFS patients, and pregnant women. 1998 1994 d

(Continued From Previous Page)
Activity requested Year( s) requested Year( s) started 57
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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 Response to Congressional
Committee Requests for CFS Activities

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. 58
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Table 8: Congressionally Requested CFS Activities for NIH
Activity requested Year ( s) requested Year started
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 virus syndrome. 1988 1991
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 laboratory data on patients. 1990 1991

Issue a request for applications on CFS to increase the number of extramural research grants funded. 1990 1991
Solicit and fund additional research grants. 1991 1991
Initiate a consortium of research centers for CFS research, preferably at the Universities of Nevada and Minnesota. 1991 1992

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 systems. 1991
Designate reference laboratories and facilitate data exchange among institutions in the geographic areas in which CFS concentrates. 1991

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 conduct basic and clinical research on CFS. 1993 1993

Ensure that individuals who have expertise in CFS or neuromuscular diseases and are representative of a variety of disciplines and fields are appointed to appropriate NIH advisory committees and
boards.
1993, 1998, 1999 1993

Establish procedures to enable the patient community to provide input to the direction of CFS research at NIH. 1993 1993
Consider increasing opportunities for CFS patients and researchers to participate in advisory committees. 1993 1993
Conduct studies that continue to look into retrovirus activity and other areas of infectious disease pathogenesis. 1994 1994 59
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a Workshop.
b Recompeted.

Direct resources to extramural grants focused on promising areas of biomedical research and to investigations seeking to identify etiological agents and markers for the pathophysiology of CFS. 1996, 1998 1996
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 execution of the workshop on pediatric CFS. 1998 1998

Recommend that the Office of Research on Women's Health develop a strategy to address chronic pain syndromes in women. 1998 1998 a
Use all mechanisms, including program announcements, to study all facets of pediatric CFS. 1999 1996
Address care needs, including the education of providers in assessment, diagnosis and treatment, case management, and rehabilitative efforts. 1999

Establish chronic fatigue assessment and treatment centers. 1999 1999 b

(Continued From Previous Page)
Activity requested Year ( s) requested Year started 60
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Appendix VI
External Review Recommendations to CDC and NIH Appendi xVI

Recommendations to CDC 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.)

Table 9: Recommendations From CDC's 1996 Peer Review and Agency Response
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, and CDC should regularly
inform NIH about ongoing progress and the results of its ongoing studies. It appears that HHS' CFS Coordinating Committee
(CFSCC) concentrates primarily on discussing the intramural research programs at NIH and CDC.

CDC and NIH regularly provide updates to members of CFSCC and attendees at that meeting regarding their respective CFS programs.

CDC's CFS program should be regularly reviewed by an external review group. Subsequent to this 1996 review, CDC's CFS program was reviewed in 1999— the most recent external peer review.
Provided the Viral Exanthems and Herpesvirus Branch can develop additional expertise in the fields of neuroendocrinology
and neuropsychology, the placement of the CFS program within that branch continues to be appropriate.
The Viral Exanthems and Herpesvirus Branch is developing expertise in neuroendocrinology and neuropsychology through
agreements with Emory University.

CDC's CFS program should continue its ongoing active dialogue with patient advocacy groups. Meeting held at CDC in October 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 same statistical techniques (including factor analysis) should be applied to other
data sets as they emerge.

Standard operating procedure.

Investigations of potential clusters of cases should begin as early as possible after the onset of the putative outbreak to ensure the
highest likelihood of identifying an etiologic agent.
Program begins investigations of reported clusters as early as possible. Emphasis in both cluster investigations and population
studies is to detect and study incident CFS cases. 61
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CDC should write a formal assessment of the reasons for the considerable differences in the observed prevalence rates from
different studies, besides differences in the completeness of the case ascertainment techniques across the studies.
Done in discussion of newest prevalence manuscript to be submitted for publication.

CDC should comment on the possible biological implications of some of the differences in prevalence it has observed in different
age, gender, and socioeconomic groups.
Done in discussions of all appropriate manuscripts.

Future studies should focus on prevalence in children and geriatric populations. Widely repeated anecdotal evidence indicates that
teachers, airline workers, and health care workers may be differently affected. (To some extent, such possible occupational
associations have been evaluated already in the San Francisco study, but it is not clear whether the sample size of this cross-sectional
observational study allowed confident conclusions.)

—Wichita surveillance includes all residents 2 years and older. —The National Survey (planned for fall 2000) will give special
emphasis to children. —The National Survey will collect detailed information on possible
occupational associations with CFS.

CDC should continue some studies of the possible role of human herpesvirus 6 in CFS. The group strongly supports further study of
Borna disease virus. CDC should also study the relationship of other known or newly-discovered microorganisms that could, on
the basis of their association with other similar illnesses or their tissue tropism, be potential triggering agents or cofactors for CFS.

—CDC's most recent study of the possible associations between CFS and human herpesvirus 6 and 7 found no association.
—CDC supported additional studies of Borna disease virus, which found no associationwithCFS.
—The Viral Exanthems and Herpesvirus Branch is developing expertise in identification and characterization of novel infectious
agents possibly associated with CFS.
A regular formal process should be instituted for reviewing and updating information for the public. In particular, these updates

should reflect all published research, whether conducted at CDC or elsewhere.
Standard operating procedure for CDC programs. Program does not have resources to maintain and disseminate data on all published
CFS research.

CDC's Internet web site should include a written summary of all programs and all work on CFS currently under way at CDC. Printed
copies of the information should be available to those who do not have access to the Internet. The web site might also contain a "Hot
Topic" button that provides brief, timely statements about CFS-related issues that have been highly visible in the media.

—The web site now includes a summary of all new CDC work on CFS.
—Printed copies of information are available to those without Internet access. CDC operates a CFS voice information system that
offers the option of receiving printed materials. CDC also provides suchinformation in response to writtenqueries.
—The web site contains a Hot Topics button.
Each public document about CFS and each public presentation and media interview about CFS should state clearly and

prominently that CFS is a "priority one emerging illness."
NCID no longer uses this classification.

Recommendations related to proposed future studies
Some follow-up beyond a 1-year review in Wichita should be planned with at least a sample of the cases (and noncases)

identified during the initial year. The study should attempt to assess the level of debility/ functional status in this population. The
study should also follow a sample of patients who report debilitating chronic fatigue but who do not fully meet CDC's case
definition of CFS.

—Approximately 8,000 subjects who completed detailed interviews during the initial survey have been followed for 3 years. In addition to
monitoring the clinical courses of the disease, this measures incidence of CFS.
—A manuscript describing functional status at baseline is in preparation. Following the third year of follow-up, analyses will
explore functional status over time.
The representational difference analysis technique should be used not only with peripheral mononuclear cells but also with tissue

specimens and cerebrospinal fluid, when possible.
—Program determined after review that this technique was not the most appropriate method and is using other strategies.
—At present, only peripheral blood cells can be collected from subjects enrolled in population-based studies.

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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).

Table 10: Recommendations From CDC's 1999 Peer Review, Board of Scientific Counselor Review, and Meeting With Patient
Advocates, and Agency Response

Studies of stress and herpes simplex virus 1 reactivation should not be supported. Herpes simplex virus 1 reactivation protocol was stopped.
Recommendations related to possible additional research areas
CDC should develop some collaborations with neuroendocrinologists to study the hypothalamic-pituitary axis. Neuroendocrinologist should be on staff (through agreement with Emory) by September 2000.

CDC could provide an international service by offering to create a brain bank of specimens available for study, including other tissue
specimens from these same patients, when possible.
CDC will convene a meeting in fall 2000 to initiate this process.

(Continued From Previous Page)
Recommendation CDC response

Recommendations CDC response
General recommendations
Broaden collaborations. Collaborations vary depending on program at the time.
Broaden communication with Council of State and Territorial Epidemiologists, advocates. In process.

Broaden availability of patients and specimens to scientific community. Standard operating procedure, depending on program strategy and priorities and the quality of proposals.
Recommendations related to surveillance
Continue Wichita cohort beyond 3 years. Clinical cohort time frame extended.
Study quality of life, economic burden, patient management, long-term care, and behavioral and functional sequelae. A manuscript is being drafted, and CDC is hiring a medical research officer and conducting clinical studies. CDC also plans

to conduct a national survey.
Explore CFS in families and occupations. A manuscript is being drafted, and CDC plans to conduct a national survey.

Place more emphasis on adolescents. CDC is welcoming a pediatrician to 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. 63
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Source: Recommendations from CDC. CDC responses reported to GAO.
Recommendations to NIH 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

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 national survey. Survey will be designed to capture such data.
Use factor scores (chronic unwellness) to better weight symptoms and measure severity. In process and part of the 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 studies combined with brain imaging. Exploring this with Emory University.

Recommendations related to molecular epidemiology
Improve balance of gene expression analysis program. In process.
Develop a program to search for novel uncharacterized infectious agents. Was part of the April 2000 Banbury Conference, Strategies for Identification and Characterization of Unknown Pathogens,

which CDC co-organized and cosponsored.
Recognize CFS as a contagious disease that occurs in clusters. Clusters are examined on request, but CFS does not appear to be contagious.

Assess risk of transfusion transmission. A statement regarding risk has been released, and CDC continues to monitor.
Broaden investigations to consider environmental exposures/ toxicology. There is no evidence from CDC's case control studies to support 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 materials. In process with HHS' Health Resources and Services Administration.

Develop national CFS information campaign. CDC maintains a web page, publishes journal articles, and provides other information.
React to CFS articles in reviewed journals and in popular press. Standard operating procedure, when appropriate.
Explore CFS education in schools and establish liaison with the Department of Education. Will follow up, as appropriate.

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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. 65
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Appendix VII
NIH Expenditures on CFS Research, by Institute and Center Appendi xVII

Note: Dollars in thousands.
a Funding 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.

b NIMH 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.

c Due to rounding, figures in total column may not be the sum of institutes' and centers' yearly
expenditures.

Fiscal year NCI NCRR a NHLBI NIAID NIAMS a NICHD a NIMH b NINDS a Tot al c
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 66
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Appendix VIII
NIH Activities in Support of CFS Research Appendi xVI II

NIH has issued four programannouncements 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. 1 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. 2

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

1 At the time, some experts believed there might be a relationship between CFS and Epstein-Barr
virus.

2 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. 67
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Appendix VIII NIH Activities in Support of CFS Research
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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. 3 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

3 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. 68
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Appendix VIII NIH Activities in Support of CFS Research
Page 67 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
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 Grant Process 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. 69
69 Page 70 71
Appendix VIII NIH Activities in Support of CFS Research
Page 68 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
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. 70
70 Page 71 72
Page 69 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
Appendix IX
Comments From the Department of Health and Human Services Appendi xIX 71
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Appendix IX Comments From the Department of Health
and Human Services

Page 70 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
See comment 1, p. 73. 72
72 Page 73 74
Appendix IX Comments From the Department of Health
and Human Services

Page 71 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
See comment 2, p. 73.
See comment 3, p. 73.

See comment 4, p. 73.

See comment 5, p. 73. 73
73 Page 74 75
Appendix IX Comments From the Department of Health
and Human Services

Page 72 GAO/ HEHS-00-98 Chronic Fatigue Syndrome 74
74 Page 75 76
Appendix IX Comments From the Department of Health
and Human Services

Page 73 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
GAO Comments 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 75
75 Page 76 77
Appendix IX Comments From the Department of Health
and Human Services

Page 74 GAO/ HEHS-00-98 Chronic Fatigue Syndrome
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) Lett er 76
76 Page 77 78

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