|
Release
Date: |
April
30, 2001 |
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RFA:
AT-01-004 |
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National
Center for Complementary and Alternative Medicine |
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Letter
of Intent Receipt Date: |
July 18,
2001 |
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Application Receipt Date: |
August
29, 2001 |
The National Center for Complementary and Alternative
Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI)
invite applications for a multi-site, randomized, double-blinded,
placebo-controlled trial investigating the efficacy and safety of EDTA
(ethylene diamine tetra-acetic acid) chelation therapy in individuals
suffering from Coronary Artery Disease (CAD). It is estimated that more than
800,000 visits for chelation therapy were made in the U.S. in 1997. If
chelation therapy is safe and effective in treating CAD it would represent a
new therapeutic modality that would gain widespread application. However, if
chelation therapy is ineffective, these data will provide important
information to the U.S. public and allow for informed decision making
concerning continued use of EDTA for CAD.
The Public Health Service (PHS) is committed to achieving
the health promotion and disease prevention objectives of "Healthy People
2010," a PHS-led national activity for setting priority areas. This Request
for Applications (RFA), EDTA Chelation Therapy for Coronary Artery Disease,
is related to one or more of the priority areas. Potential applicants may
obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.
Applications may be submitted by domestic and foreign,
for-profit and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government. Racial/ethnic
minority individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
This RFA will use the cooperative agreement (U01)
mechanism. The cooperative agreement is an assistance mechanism in which NIH
will have substantial involvement with the recipient during the performance
of the planned activity. The nature of the NIH's involvement is described
under the "Terms and Conditions" of the award. Primary responsibility for
the planning, direction, and execution of the proposed project will be that
of the applicant/awardee.
The total project period for applications submitted in
response to the present RFA may not exceed five years. The anticipated award
date is March 1, 2002.
Up to $30,000,000 (total cost) over the entire project
period is available to support this initiative. It is expected that one
award will be made. The NCCAM and NHLBI intend to commit approximately $6
million in FY 2001 to fund one new grant in response to this RFA. An
applicant may request a project period of up to 5 years and a budget for
total costs of up to $6 million per year. Because the nature and scope of
the research proposed may vary, it is anticipated that the size of this
award will also vary. Although the financial plans of the NCCAM and NHLBI
provide support for this program, awards pursuant to this RFA are contingent
upon the availability of funds and the receipt of a sufficient number of
meritorious applications. At this time, there are no plans to reissue this
RFA.
CAD is the leading cause of mortality for both men and women in the United
States. The prevalence of coronary heart disease is estimated at 12 million,
including 7 million suffering from acute myocardial infarction and 6.2
million with angina pectoris (NHLBI 1998 Chartbook). More than 500,000
Americans die of heart attacks each year. Common conventional medical
treatments for CAD include percutaneous transluminal coronary angioplasty
(PTCA) and coronary artery bypass graft (CABG) surgery, procedures that are
invasive and costly. Chelation therapy has been used by some physicians for
treatment of atherosclerosis, although compelling evidence indicating
treatment efficacy is absent.
Chelation refers to the formation of metal complexes by the bonding of a
chelating agent or ligand with a metal to form a heterocyclic ring.
Initially, the medical use of chelating agents was to treat heavy metal
poisonings, for example, British Anti-Lewisite (2,3-dimercaptopropanol) for
arsenical poisoning (1) and citrate for lead intoxication (2).
Another chelating agent, ethylene diamine tetraacetic acid (EDTA) was also
used to treat lead poisoning in a young child (3) and
following its initial approval by the Food and Drug Administration (FDA) in
1953, EDTA was utilized to treat hypercalcemia, other heavy metal poisonings
(4-6), and metastatic calcification (7).
Originally, it was a clinical observation that EDTA
appeared to reduce symptoms of angina pectoris (8) and it
was also noted that it affected cholesterol metabolism (9,10).
Subsequently, EDTA was advocated by some physicians to treat symptoms of
atherosclerotic disease. In some studies, clinical measures of efficacy such
as exercise time, ankle-brachial index, and arteriograms have been reported
in addition to subjective data. Chelation has been used most widely in
peripheral vascular disease, but also in coronary artery disease, and
cerebrovascular disease. However, few controlled data are available that
speak to the usefulness of chelation in the treatment of heart or vascular
disease (11-17).
EDTA is a tetrabasic acid with 4 replaceable hydrogen ions. Importantly, it
is poorly soluble in water but it is soluble in alkaline hydroxides. In the
US, the commercially available salts are the disodium and the calcium
disodium salts of EDTA. In these formulations, EDTA is widely used as an in
vitro anticoagulant for blood collection and as an antioxidant synergist,
stabilizer and preservative for pharmaceutical preparations. For chelation
therapy, the most widely used formulation is a protocol recommended by the
American College for Advancement in Medicine (ACAM) (18)
that includes disodium EDTA and magnesium chloride. This formulation has yet
to be tested in rigorous randomized controlled trials.
EDTA chelates various divalent metal ions with differing
affinities. It is poorly absorbed from the gastrointestinal tract. Following
intravenous administration, EDTA is found primarily in plasma. It is
distributed in the extracellular fluid, and it does not appear to penetrate
cells. Only about 5% of the plasma concentration is found in spinal fluid.
The half life is 20-60 minutes. It is excreted mainly by the kidney, with
about 50% excretion in one hour and more than 95% within 24 hours. Almost
none of the compound is metabolized. Treatment with EDTA has a low incidence
of side effects. The most common side effect reported is a burning sensation
experienced at the infusion site. Relatively rare adverse effects include
phlebitis at the infusion site, malaise, fever, hypotension, hypocalcemia,
headache, nausea, vomiting, diarrhea, insulin shock, bone marrow depression,
prolonged prothrombin time and cardiac arrhythmia. Cases of renal toxicity
have also been reported.
Mechanisms involved in the pathogenesis of atherosclerosis include
proliferation of smooth muscle cells, abnormalities of lipid metabolism, and
endothelial dysfunction. However, historically, calcium deposition was also
believed to be important in the development of atheroma. There is an
age-associated increase in calcium deposition in the arterial wall. The
hypothesis is that EDTA will chelate calcium from atheromatous plaques and
thus favorably alter the plaque and the arterial wall, for example by
altering endothelial function (19). Other postulated
mechanisms of EDTA action include a) inhibition of platelet aggregation (20),
b) stimulation of parathormone (PTH) release that in turn mobilizes calcium
from plaques and reduces progressive calcification, c) an antioxidant effect
by complexing with transitional metals thus interfering with free radical
production and lipid peroxidation, d) effects on serum iron (21),
and e) transient lowering of serum cholesterol. Some of these hypotheses may
be valid, but there are no confirmatory mechanistic studies.
The use of chelation therapy in coronary artery disease is limited to 12
descriptive studies and four randomized control trials (RCT) (7,
22-33). Although each of the descriptive studies reported
a reduction in angina, they are uncontrolled clinical observations or
retrospective data, typically with small numbers of patients. Two of the RCT
were underpowered to detect a difference, a third RCT did not publish a
final paper, and the fourth noted exercise improvement but was limited to 10
subjects.
Most of the EDTA chelation studies have focused on peripheral vascular
disease and are a combination of RCTs and descriptive studies. These RCT's
have not demonstrated significant benefit but they were underpowered to
detect a small effect and each trial has been criticized by some for
methodological problems. Observational reports of the use of EDTA in
peripheral vascular disease suggest that chelation can increase exercise
duration but in the absence of a placebo control group, spontaneous
symptomatic improvement cannot be excluded (7,8,11-17,
22, 25, 29-32,
34-45).
The use of EDTA chelation has been reported in patients with cerebrovascular
disease. The claims of efficacy with EDTA therapy are based on subjective
clinical improvement and in some studies, improved cerebral perfusion or
reduction in degree of carotid stenosis (22,25,26,30,34,
36,39,46-48).
Typically, however, the patient populations were small and had a variety of
cerebral diseases; most importantly, the studies were without appropriate
controls, and in some, there was criticism of methodology. Particularly in
the older data, the observations tended to be subjective and descriptive.
There are no appropriate randomized trials of EDTA in the treatment of
cerebrovascular disease. Altogether, there are no substantial data to
support claims of efficacy.
A protocol for an RCT of chelation therapy in peripheral vascular disease
was developed with FDA approval. The study involved assessment of exercise
tolerance in 3 experimental groups that were to receive infusions of
magnesium alone, or 1 gram of EDTA and magnesium or 3 grams of EDTA and
magnesium. Unfortunately, recruitment was slow and within 3 years the study
was terminated with recruitment of only about 25% of the total projected 120
subjects. No useful data were obtained (49-51). A second
RCT was planned in Texas by Baylor College of Medicine and the University of
Texas Medical School but the study was never conducted and the results of a
pilot study in 18 patients only reported the effects of EDTA on the
parathyroid gland (52). Currently, there is an ongoing
Canadian RCT (PATCH-EDTA) designed to assess exercise time in 80 patients
with coronary artery disease randomly allocated to EDTA or placebo.
OBJECTIVES
The objective of this initiative is to strengthen the knowledge base
regarding efficacy and safety of EDTA chelation therapy for persons with CAD
through the use of rigorous trial design and validated outcomes measures.
Areas to be considered by applicants include the
following:
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Development of control/comparison groups that are
appropriate for this project.
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Determination of the efficacy of EDTA chelation therapy in
treating CAD on average and in various sub-populations.
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Determination of the safety of EDTA chelation therapy.
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Use of assays to determine metabolic changes in human
subjects that may provide information on the potential mechanisms of
action of EDTA chelation therapy.
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General
Although objectives of the RFA can be met through the initiation of a
full-scale, randomized, two-arm, double- blind, placebo-controlled,
multi-site trial of EDTA Chelation therapy, other designs, including
additional treatment arms, will be considered if sufficiently justified.
While it is expected that the trial will investigate the EDTA Chelation
treatment protocol recommended by ACAM, other protocols can be proposed if
justified and adequately supported by the literature. A detailed
description of the proposed intervention must be provided. Adequacy of
blinding must be described.
The study should consist of four phases: 1) an initial phase during
which the protocol is finalized (e.g., study procedure and Manual of
Operations, data collection manuals, data management, training,
establishment of the Data and Safety Monitoring Board, etc.) by the trial
Steering Committee (see "Special Requirement"); 2) a recruitment period;
3) a period of intervention and follow-up; and 4) data analysis and
dissemination.
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Outcomes
Plans for patient follow-up and choices of outcome measures should be well
defined and clearly justified. Justification and definition of endpoints
for the proposal should be provided. Appropriate objective endpoints
include mortality, myocardial infarction, stroke, and hospitalization for
unstable angina or revascularization. Other outcome measures could
include, but are not limited to:
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general health status/quality-of-life indicators;
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mechanistic studies, including but not limited to, plasma
markers of oxidative stress, endothelial activation/inflammation and
intermediate endpoints such as platelet aggregation, serum
concentrations of iron, cholesterol and free calcium; and
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health care utilization (e.g., increased or decreased use
of other medications or office visits; cost-effectiveness data).
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Inclusion/Exclusion Criteria
Inclusion and exclusion criteria (including preexisting medical conditions
and the use of counter-indicated drugs) should be identified and justified
by the applicant; in general, these criteria should address exclusion of
individuals who might be harmed by participation in the trial, or who are
likely to be poor compilers. A database should be maintained on all
potentially eligible subjects who were identified but not enrolled,
including the reasons for their exclusion or refusal to participate. Based
on the patient profile for CAD, children are excluded from this study.
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Compliance
Research designs that maximize patient compliance should be described and
justified in the application.
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Recruitment
For all proposed trial sites, applicants must demonstrate the ability to
recruit and randomize the required number of study participants, be able
to implement the various study procedures, and provide evidence of the
ability to maintain high rates of follow-up during the course of the
trial.
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Sample Size and Power Calculations
To ensure acceptable statistical power, the clinical trial design should
include an adequate number of participants and should be of sufficient
duration to address the study questions of efficacy, safety, tolerability
and acceptability, as well as any other secondary research questions. To
this end, expertise in biostatistics and clinical trial design are
essential during the planning phase of the study. Study size and duration
will vary according to specific study hypotheses, target population and
endpoints; as such, the study size and duration should reflect both the
choice of outcome measures and the predicted effect sizes. Sample size
calculations should include the possibility of interim analyses of the
data. Given these parameters, it is understood that the calculated sample
size may underpower (or overpower) the study.
The applicants should discuss ways they might directly assess the
adequacy of their sample size calculations (e.g., through internal or
external pilot studies) and make appropriate adjustments in recruitment
and/or follow-up as necessary.
Steering Committee
A Steering Committee will be established to serve as the main governing body
of the trial. Trial sites will be required to accept and implement the
protocol and procedures approved by the Steering Committee. Descriptions of
Committee membership, scheduling, responsibilities and authority are listed
under "TERMS AND CONDITIONS OF THE AWARD."
Executive Committee
The Executive Committee, composed of the Steering Committee Chair,
Coordinating Center Principal Investigator, the NCCAM Program Officer, an
NHLBI Scientific Adviser and the Awardee will make recommendations to the
Steering Committee regarding study conduct. The Awardee will serve as chair
of the Executive Committee. The Executive Committee will meet to monitor
study progress and to review non-endpoint data. Executive Committee meetings
will be scheduled for the day prior to Steering Committee meetings. The
recruitment progress of each center and of the whole trial will be updated
bimonthly by the Awardee for the Executive Committee. Other reports for the
Executive Committee may be requested of the Steering Committee as needed. In
any votes of the Executive Committee, each member will have a single vote.
Data and Safety Monitoring Board
An independent Data and Safety Monitoring Board will be appointed by the
Director of NCCAM with input from the Awardee. Descriptions of Board
membership, scheduling, responsibilities, and authority are listed under "TERMS
AND CONDITIONS OF THE AWARD."
Minimum Requirements for Application
Each application must include the following elements; applications that fail
to meet these requirements will be considered unresponsive to the RFA and
will not be reviewed:
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Investigators
The application must name a single Principal Investigator (PI) who will
have scientific responsibility for the application as a whole, including
all consortium-related research activities. The PI is required to commit a
minimum of 10% effort to these administrative duties. In addition, the PI
is the Senior Investigator (see below) from his or her Institution and
will be expected to commit 10% effort to these scientific activities,
bringing her or his total commitment to 20% effort (10% administrative and
10% scientific). The PI must have substantial experience in the treatment
and management of CAD and in the design, implementation and evaluation of
clinical trials. Such experience must be documented in full. Biographical
sketches for all key investigators must be provided. In addition,
applications must name a Senior Investigator for each trial site in the
consortium that will be responsible for on-site clinical and scientific
implementation, direction and management of the trial protocol, as well as
the coordination of requirements for any adjunct studies of underlying
mechanisms and surrogate markers. Senior Investigators are required to
commit at least 10% effort to this trial. Senior Investigators must have
substantial experience in the treatment and management of CAD and in the
design, implementation and evaluation of clinical trials. The application
should also name a Trial Manager (or Coordinator) who is an individual
with substantial technical/administrative experience in managing patient
enrollment, patient follow-up, and multi-source data collection for
clinical studies, such as an experienced nurse manager. Each trial site
associated with the trial may also name a Trial Site Manager (or
Coordinator) if adequately justified. The application can also include an
Administrative Manager to handle budgetary, IRB and sub-contract issues as
appropriate and justified.
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Trial Organization and Administration
The trial group will be an identifiable organizational unit formed by a
consortium of cooperating institutions. Such a unit will involve the
interaction of broad and diverse elements. Therefore, lines of authority
and sanction by the appropriate institutional officials must be clearly
specified. Specifically, the applicant must provide: a clear, concise
plan, in narrative and diagrammatic form, that depicts the
interrelationships among the members of the consortium, their relevant
experience/expertise, and the contribution of each to fulfillment of the
objectives of this RFA; an organizational chart of the consortium showing
the name, organization, and scientific discipline of the PI and of all key
scientific, technical and administrative personnel; and a mechanism for
selecting and replacing key professional or technical personnel. Include a
description of the role, responsibility and authority of the PI, Senior
Investigators and Trial Manager. The application must include a written
commitment to accept the participation and assistance of NCCAM staff in
accordance with the guidelines outlined under "Terms and Conditions of
Award: NCCAM Staff Responsibilities." The application must also include a
signed letter from the PI and all Senior Investigators that states: a)
their commitment to this cooperative trial; b) their willingness to serve
on the Steering Committee and to adhere to the decisions reached by that
Committee, including following the finalized protocol and adjunct studies;
and c) their commitment that recruitment of patients for the EDTA
chelation trial will take precedence over any subsequent clinical trials
started after the EDTA chelation trial is awarded.
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Preliminary Studies
Data that show the feasibility of the trial should be presented; this
should include prior examples of patient recruitment, retention and
follow-up. Additional supporting data from other research should be
included so that the approach chosen is clearly justified.
Conceptualization and planning must have progressed to a stage sufficient
to allow for an overall assessment of the likelihood of the trial's
success.
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Patient Availability and Recruitment
The applicant institution and each institution participating in the trial
must: document their experience and capacity to recruit and retain study
participants; provide a description of the population currently available
for the proposed protocol; describe the procedures for screening this
population to identify eligible individuals, for recruiting these
individuals into the trial; and describe proposed mechanisms for
monitoring accrual performance and criteria for continued participation by
each participating institution.
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Data Coordination, Management and Quality Control
Applicants should document their previous experience and must present:
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a plan for randomization, data coordination, data
collection and management across trial sites;
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a rationale for the need for a Data Coordinating Center
to interact with, and coordinate among, multiple trial sites and a
description of the responsibilities of the Data Coordinating Center;
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a plan describing development of appropriate placebo
control group(s);
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a description of the proposed intervention(s) and outcome
measures;
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methods for monitoring the quality and consistency of the
intervention and outcome measures;
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protocols for data collection, formatting and
transmission to and from individual trial sites; prototypes of data
collection forms should be included in an appendix;
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a comprehensive set of procedures to assure data quality
and also procedures to assure confidentiality of subjects;
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a plan for training programs to educate staff at trial
sites about operating procedures with the goal of maximizing efficiency
of data operations;
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data quality control systems;
In addition, the applicants should provide evidence of their prior
management capability to:
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estimate appropriate and reasonable resources needed for
the EDTA chelation trial;
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manage resources efficiently during the research;
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adjust assigned resources to changing demands as the
research work progresses;
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keep NCCAM informed of changes of resource allocations;
and
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subcontract with affiliated trial sites or other outside
organizations.
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Adverse Events
All studies must have a structured adverse event determination, monitoring
and reporting system, including standardized forms and protocols for
referring and/or treating subjects experiencing adverse events. The
proposed schedule for reporting adverse events to the DSMB, the NCCAM
Program Officer and/or the FDA should be described.
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Reporting and Publications
The PI will be required to submit quarterly progress reports to the NCCAM
and the DSMB. These reports should include recruitment data, indices of
quality control, reports of significant side effects or morbidity
(previously reported to the DSMB, the NCCAM Program Officer and the FDA),
and deviations from the protocol. Such reports are in addition to the
annual awardee noncompeting continuation progress report. The DSMB (see
Terms and Conditions of Award) may require additional information. The PI
also will be requested to present both a mid-term and final report to the
NCCAM Advisory Council.
The following terms and conditions will be incorporated
into the award statement and provided to the Principal Investigator as well
as to the institutional officials at the time of the award. These special
Terms and Conditions of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS grant administration
regulations in 45 CFR part 74 and 92, and other HHS, and NIH grant
administration policy statements.
The administrative and funding instrument used shall be a
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NCCAM scientific and/or
programmatic involvement with the Awardee is anticipated during performance
of the activity. Under the cooperative agreement, the purpose of the NCCAM
is to support and/or stimulate the recipient's activity by involvement in
and otherwise working jointly with the award recipient in a partner role,
but it is not to assume direction, prime responsibility, or a dominant role
in the activity.
Consistent with the above concept, the dominant role and
prime responsibility for the activity reside with the Awardee for the
project as a whole, although specific tasks and activities in carrying out
the studies will be shared among the Awardee, other study investigators and
the NCCAM Program Officer.
Under the cooperative agreement, a relationship will exist
between the recipient of this award and the NCCAM, in which the performers
of the activities are responsible for the requirements and conditions
described below, and agree to accept program assistance from the NCCAM
Program Officer.
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Awardee(s) Rights and Responsibilities. The Awardee(s) will
retain custody of and have primary rights to the data developed under
these awards, subject to Government rights of access consistent with
current DHHS, and NIH policies. The Awardee will have substantial and lead
responsibilities in all tasks and activities. These include protocol
development, data collection, quality control, final data analysis, and
assistance with preparation of publications. The Awardee agrees to work
cooperatively with the NCCAM, and agrees to accept guidance from the trial
Executive and Steering Committees, and to follow the Manual of Operations
approved by the Steering Committee, DSMB and NCCAM. At the time of award,
the Awardee will be requested to nominate prospective DSMB members to the
Director of NCCAM, who will select the DSMB members; other specific
Awardee responsibilities are described below:
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Data Coordination and Management
The Awardee will be responsible for ensuring the provision of
centralized data management and coordination assistance for this trial.
Under the direction of the Steering Committee, the Awardee (or its
designee) will provide technical assistance and data management services
to the trial sites with respect to quality control, uniformity of data
collection, management of the collective database, and data analysis.
Each trial site will be responsible for providing the Awardee with
all primary study data for management, quality control and analysis,
using procedures and standards determined by the Steering Committee.
Specific analyses to be performed by the Awardee will be directed by the
Steering Committee.
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Quality Control and Data Assurance
The Awardee must follow procedures developed by the Steering Committee
for the prevention and/or identification of false or otherwise
unreliable data and for quality assurance of data collected by the trial
sites. The Awardee must follow Steering Committee procedures for the
assurance of data quality and quality control in accordance with
Steering Committee FDA and NCCAM guidelines.
The Awardee is responsible for ensuring that all trial sites have
routine independent audits. These audits should, at a minimum, include
the auditing of primary subject records over the course of the trial to
verify conformance with eligibility criteria, recruitment and outcome
data, and adverse events, as well as to monitor for non-compliance with
protocol or regulatory requirements, or possible alteration of data and
other discrepancies that become apparent. In the event that the NCCAM
determines that the Awardee failed to comply with these guidelines, the
accrual of new patients at the sites shall be suspended immediately upon
notice of the NCCAM determination. The suspension will remain in effect
until the Awardee conducts the required audit and the audit report or
remedial action is accepted by the NCCAM. In the event that the audit
identifies discrepancies or misconduct, these findings must be reported
the NCCAM Project Officer, the Awardee and the DSMB within two weeks.
All accrual at the non-complying trial site(s) will be suspended until
remedial action is taken and accepted by the NCCAM. The Awardee will be
responsible for notifying any affected trial sites of the suspension.
During the suspension period, no funds from this award may be provided
to the trial site(s) for new accruals, and no charges to the award for
new accruals will be permitted. The NCCAM will also notify the PI's
institution that is the direct recipient of a cooperative agreement from
the NCCAM if it is necessary to suspend accrual at that institution or
at a third party institution supported under that institution's
cooperative agreement.
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Protocol Closure
The Awardee, in consultation with the DSMB, shall establish and
implement mechanisms for interim monitoring of results and monitoring
protocol progress. If the DSMB wishes to close accrual to a study prior
to meeting the initially established accrual goal, the interim results
and other documentation should be made available to NCCAM staff for
review and concurrence prior to implementation of the recommendation by
the DSMB. It is recommended that statistical guidelines for early
closure be presented as explicitly as possible in the protocol in order
to facilitate these decisions.
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Procedures in the Event of Scientific Misconduct
If a duly authorized governmental or institutional body issues a final
determination that scientific misconduct has occurred or if the Awardee
determines that other events have occurred which have significantly
affected the quality or integrity of the trial data or patient safety,
the Awardee is responsible for notifying the DSMB, the NCCAM, the
collaborating investigators, the appropriate Institutional Review Boards
(IRBs), the FDA and other sponsors of the affected work.
The Awardee is also responsible, if the events described above have
occurred, for ensuring that submitted but unpublished abstracts and
manuscripts are corrected, if possible. If publication deadlines have
passed or if abstracts and/or manuscripts containing the affected data
have already been published, the Awardee is responsible, within 90 days
after learning of the event(s) significantly affecting the quality of
the trial data or patient safety, for submitting to NCCAM a re-analysis
of the results deleting the false or otherwise unreliable data, and
disclosing within the text the reason(s) for the reanalysis. The Awardee
must submit the reanalysis for publication. In addition, true copies of
data files and other supporting documentation from studies affected by
scientific misconduct or other findings affecting the quality or
integrity of data or patient safety shall be made available to the NCCAM
in a timely manner upon request by the NCCAM Program Officer. The NCCAM
reserves the right to reanalyze, to publish, or to distribute its
analyses of these data when it is in the interest of public health.
Prior to release, publication or distribution of such analyses, the
NCCAM will provide such analyses to the awardee. The Awardee must use
its best efforts to notify all scientists, research laboratories, and
other organizations to which the awardee has sent research materials
affected by false or otherwise unreliable data.
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Reporting Requirements
Interim reports of the trial and adjunct studies shall appear in the
minutes of each Steering Committee meeting and shall include specific
data on patient accrual. Quarterly accrual information must be provided
by the Steering Committee to NCCAM and the DSMB. A system for providing
such information in a timely manner should be in place. Participants
must provide accrual data to the Steering Committee in accordance with
Steering Committee procedures. All recipients of NCCAM support for
clinical trials, including trial sites responsible for coordinating and
monitoring such trials, must promptly notify the NCCAM, the FDA and any
other sponsors of the trial of adverse events (i.e., adverse drug
reactions) according to directions provided in the adverse event
reporting section of the protocol. The Awardee will notify all
institutions/investigators participating in this project, about the
above requirement and about the institutions'/investigators'
responsibility to report adverse events as specified in the protocol.
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Federally Mandated Regulatory Requirements
Each trial site participating in a consortium arrangement is required to
meet the DHHS and NIH regulations for the protection of human subjects
and FDA requirements for the conduct of research using investigational
agents. At a minimum, these include:
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methods for assuring that each institution at which
site investigators are conducting clinical studies has a current,
approved assurance on file with the Office for Human Research
Protections (OHRP); that study protocols are reviewed and approved by
the responsible registered IRB prior to patient entry; that active
protocols are reviewed at least annually by the IRB; and that all
protocol amendments are approved by the IRB.
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methods for assuring or documenting that each patient,
or patient's parent/legal guardian, gives fully informed consent to
participation in a research protocol prior to the initiation of the
experimental intervention. All informed consent documents must be
available for review upon request by the NCCAM or Steering Committee,
or FDA or Industry sponsor, if applicable.
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NIH Staff Responsibilities
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Normal Stewardship
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The NCCAM will name a Program Officer whose function
will be to assist the Principal Investigator, the Executive Committee
and the Steering Committee in oversight of the trial. In addition, the
NCCAM Program Officer will retain overall administrative
responsibility for the award and will be the contact point for all
facets of interactions with the Awardee concerning such issues. In
addition, ad hoc advisory committees may be formed as needed to
assist/advise the NCCAM Program Officer.
-
A change in the PI, or in any key personnel identified
on the Notice of Award, must have the prior written approval of the
NCCAM Grants Management Specialist in consultation with the NCCAM
Program Officer.
-
The NCCAM Program Officer will assist with the review
and approval of adjunct protocols to ensure they are within the scope
of the grant and also for safety considerations, as required by
Federal regulations.
-
The NCCAM Program Officer will review the progress of
each trial site through consideration of the annual reports, site
visits, patient logs, etc. As required for these activities, the
Program Officer will be assisted by other NCCAM staff and contractors.
This review may include, but is not limited to, safety issues,
compliance with protocol, specifications, patient accrual, adherence
to uniform data collection procedures, data management and quality
control, and the timeliness of data reporting. The NCCAM Program
Officer is able to request additional data from investigators as
needed on these issues. Based on this review, the NCCAM reserves the
right to close the study (or any individual trial site(s)) to accrual,
or to terminate the study (or any individual trial site(s)) for
reasons including:
-
failure to implement the final collaborative protocol
in a timely fashion;
-
substantive changes in the agreed-upon protocol to
which the NCCAM does not agree;
-
substantial shortfall in participant recruitment,
follow-up, data reporting, quality control, or other major breech of
the protocol;
-
emergence of new information that diminishes the
scientific importance of the study question;
-
patient safety and regulatory concerns;
-
accrual goals met early and;
-
study results that are already conclusive.
-
The NCCAM Program Officer will review all DSMB reports.
As necessary, the NCCAM Program Officer will request advice of the
DSMB on study protocol and safety issues, data management, data
quality, data analysis, recruitment, retention and protocol adherence
issues arising over the course of study, and advisability of
terminating the study.
-
The NCCAM will have access to and may periodically
review all data generated under this award. The NCCAM Program Officer
reserves the option, at any point in the trial, to obtain an
independent audit of a sample of primary subject records for
comparison with the trial's regular audit reports. Auditors so engaged
will report directly to NCCAM and be reimbursed directly by NCCAM,
i.e., reimbursement will not be drawn from the award for the trial,
and costs of such audits will not be borne by the awardee
institution(s). The NCCAM Program Officer has the authority to adjust
funds provided to the trial sites as appropriate for the level of
participation in trial sites activities, including (but not limited
to) accrual. This procedure can be either prospective (i.e.,
reimbursement by the case) or retrospective (financial adjustment at
the time a non-competing continuation [Type 5] award is made).
-
Substantial Additional Involvement
-
The Program Officer will have substantial
scientific-programmatic involvement including participation in
database development, budget monitoring, modification and finalization
of the trial and any adjunct protocols, quality control, data analysis
and interpretation, preparation of publications, and coordination and
performance monitoring. The prime responsibility for these activities
resides with the Awardee although specific tasks and activities in
overseeing the studies will be shared between the awardee and the
NCCAM Program Officer.
-
Certain organizational changes require the prior
written approval of the NCCAM Program Officer. These changes include
the addition or replacement of a trial site that is associated with
this study.
-
The NCCAM Program Officer may contribute, through
review, comment, analysis, and/or co-authorship, to reporting results
of the study to interested scientific and lay organizations.
Co-authorship by the NCCAM staff will be subject to approval in
accordance with NIH policies regarding staff authorship of
publications resulting from extramural awards.
-
Collaborative Responsibilities
-
Steering Committee
A Steering Committee will be established to serve as the main governing
body of the trial. The Steering Committee will be composed of the NCCAM
Program Officer, the NHLBI Scientific Adviser, the cooperative agreement
Principal Investigator, the Trial Manager and up to five trial site
Senior Investigators (see below). At the first Steering Committee
meeting, the Chairperson will be selected by the Steering Committee from
members other than the PI or NIH staff, or alternatively, from among
experts in the field who are not participating directly in the trial. A
plan should be provided for selecting Senior Investigators to the
Steering Committee; this should include their length of term and plans
for rotation among Senior Investigators, if appropriate. Outside ad hoc
consultants will be added as appropriate and needed. All major
scientific decisions will be determined by the Steering Committee, with
the PI, Steering Committee Chair and Senior Investigators, the NCCAM
Program Officer, the NHLBI Scientific Adviser and the Trial Manager
having one vote each. The first meeting will be convened by the NCCAM
within two months of the award. The Committee will meet at least once
more during the first 12 months of the study and annually thereafter.
This Committee will have primary responsibility for finalizing the trial
protocol, and approving the design and implementation of all adjunct
studies, facilitating the conduct and monitoring of the clinical trial
and adjunct studies, analyzing and interpreting study data, reporting
study results, and setting guidelines for authorships. Each Steering
Committee member (or their surrogate) will be expected to participate in
all other Steering Committee activities, e.g., conference calls, special
subcommittees as may be necessary, etc.
The Steering Committee will be responsible for ensuring the provision
of centralized data collection, management and quality assurance. Under
the direction of the Steering Committee, the NCCAM will provide
technical assistance, as available, to the trial sites with respect to
quality control, uniformity of data collection, management of the
collective database, and data analysis. Specific data analyses to be
carried out will be determined by the Steering Committee. The results of
those analyses will be delivered to the Steering Committee as the group
responsible for determining if further analyses should be performed, how
the results are interpreted, and how the findings should be
disseminated. Applicants should include in their budget requests support
for on-site data collection and transmittal, as well as for centralized
data collection and management.
Each trial site will follow the procedures required by the final
protocol generated by the Steering Committee regarding study conduct and
monitoring, patient management, data collection, data management, data
analysis and quality control. Trial sites will be required to accept and
implement the common protocol and procedures approved by the Steering
Committee. The Steering Committee will establish mechanisms for
assessing performance of the trial sites, including institutions
participating in consortia arrangements, with particular attention to
accrual of adequate numbers of eligible patients, timely submission and
quality of required data and conscientious observance of protocol
requirements. At a minimum, this will include:
-
assessment of protocol adherence, treatment
administration, and measurement of outcomes;
-
tracking and reporting of patient accrual and adherence
to defined accrual goals;
-
ongoing assessment of case eligibility and
availability;
-
timely medical review and assessment of patient data;
-
rapid reporting of morbidity, and measures to ensure
communication of this information to all interested parties;
-
interim evaluation and consideration of measures of
outcome as consistent with patient safety and good clinical trials
practice;
-
timely communication of study results to NCCAM, the
scientific community and the U.S. Public; and
-
an on-site quality control and safety monitoring
program.
The Steering Committee shall establish and follow policies and
procedures for, and conducting periodic review of, the performance and
membership status of each trial site. This review should examine
scientific contributions, patient accrual, data accuracy and timeliness,
protocol compliance, long-term patient follow-up and audit results.
These procedures should be as simple as appropriate in order to
encourage maximum participation of physicians entering patients and to
avoid unnecessary expense. This information will be made available to
the NCCAM in a timely fashion.
-
Publication and Presentation of Study Findings
Timely publication of major findings is encouraged. Publications and
oral presentations of work performed under this agreement will require
appropriate acknowledgment of both the trial sites and NCCAM support.
Analyses to be performed using the collective data from all trial sites
will be determined and directed by the Steering Committee, as will
policies for authorship on any subsequent publications. Trial sites
wishing to perform analyses of local data will inform the Steering
Committee of any such analyses prior to initiation in order to avoid
duplication. Review and approval by the Steering Committee will be
required for all analyses, including that of local data by individual
trial sites, prior to publication or presentation according to criteria
that will be developed by the Steering Committee. The Steering Committee
may establish a Publications Subcommittee to serve this function. The
NCCAM Project Officer will have access to data generated under this
Cooperative Agreement and may periodically review the data and progress
reports. NCCAM Staff may use information obtained from the data for the
preparation of internal reports on the activities of the study. However,
the Awardee will retain custody of and have primary rights to all data
developed under these awards.
-
Investigational Drug Management
It is the sole responsibility of the applicant to obtain all necessary
clearances from the Food and Drug Administration as required, including
completion of an Investigational New Drug (IND) application. Applicants
are strongly encouraged to consult their local Institutional Review
Boards (IRB) concerning IND status and the IRB approval process. It is
important to note that neither IND or IRB approval is required prior to
submission of an application. IRB approval, is required at the time of
award. Provisional IRB approval contingent on a successful IND
application is acceptable. In addition, all trial sites are expected, in
cooperation with the NCCAM, to comply with all FDA monitoring and
reporting requirements for investigational agents.
-
Data and Safety Monitoring Board
An independent Data and Safety Monitoring Board will be appointed by the
Director of NCCAM, with input from the Awardee, and meet at least twice
a year. DSMB meetings will be open only to designated NCCAM staff and
other individuals who have been approved to have access to unmasked
data. The DSMB will be composed of experts in relevant medical,
botanical, statistical and bioethical fields who are not otherwise
involved in the trial. An NCCAM staff member other than the designated
trial Program Officer will serve as the Executive Secretary of this
Board. The Board will oversee participant safety, evaluate results,
monitor data quality, adverse events and patient accrual, and provide
operational and policy advice to the Steering Committee and the Director
of NCCAM regarding the status of the study. The DSMB will document
progress in written reports at least twice annually to the Director of
NCCAM through the NCCAM Program Officer, and will provide periodic
supplementary reports to designated NIH staff upon request.
The initial tasks of the DSMB are to review the entire protocol and
informed consent forms with regard to subject safety; identify needs for
protocol modification; review the Manual of Operations; and, after
receipt of a satisfactory protocol, recommend to the NCCAM initiation of
expenditure of project funds. The DSMB will also identify the relevant
data parameters to be reported by the Awardee and the Steering Committee
to the DSMB, and the format of these data. Subsequently, it must meet on
a regular schedule (not less than twice a year) over the course of study
(with additional meetings as needed) to:
-
Review data (including masked data) relating to
recruitment, randomization, compliance, retention, protocol adherence,
trial operating procedures, form completion, intervention effects,
auditing of primary subject records, data management, quality control,
and subject safety;
-
Identify problems relating to safety over the course of
the study;
-
Identify needs for additional data relevant to safety
issues and request these data from the study investigators;
-
Review unmasked outcome data as needed and appropriate
over the course of the trial;
-
Propose appropriate analyses and periodically review
developing data on safety and endpoints;
-
At each meeting, consider the rationale for
continuation of the study, with respect to progress of randomization,
retention, protocol adherence, data management, safety issues, and
outcome data, if relevant, and make recommendation to the Director of
NCCAM for or against continuation of the trial.
-
Provide advice on issues regarding data discrepancies
found by the data auditing system or other sources. If the NCCAM
Program Officer requests this advice, it should be provided in writing
within two weeks of the date of this request.
-
Send the NCCAM Program Officer written reports
following each DSMB meeting, and additionally as needed, on all issues
reviewed by the DSMB
At the time of award, the Awardee will be requested to nominate
prospective DSMB members to the Director of NCCAM. The NCCAM reserves
the right to appoint additional members to the DSMB to include
scientific expertise in topic areas relevant to the trial such as
biostatistics, ethics, or patient advocacy. The NCCAM Program Officer is
charged with facilitating implementation of DSMB recommendations by the
NCCAM and with conveying DSMB recommendations and requests to the
Awardee. The trial sites must comply with the approved policies and
procedures of the DSMB.
-
Arbitration
Any disagreement that may arise in scientific-programmatic matters between
award recipients and NCCAM may be brought to arbitration. An arbitration
panel will be composed of three members--one selected by the Steering
Committee (with NIH members not voting) or by the individual awardees in
the event of an individual disagreement, a second member selected by NCCAM
and the third member selected by the two prior members. This special
arbitration procedure in no way affects the awardee' right to appeal an
adverse action that is otherwise appealable in accordance with the PHS
regulations at 42 CFR part 50, Subpart
It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all
NIH-supported biomedical and behavioral research projects involving human
subjects, unless a clear and compelling rationale and justification are
provided indicating that inclusion is inappropriate with respect to the
health of the subjects or the purpose of the research. This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing research involving human
subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research," published in the NIH Guide for
Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html);
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:
The revisions relate to NIH defined Phase III clinical trials and require:
a) all applications or proposals and/or protocols to provide a description
of plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable;
and b) all investigators to report accrual, and to conduct and report
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
All applications and proposals for NIH funding must be
self-contained within specified page limitations. Unless otherwise specified
in an NIH solicitation, internet addresses (URLs) should not be used to
provide information necessary to the review because reviewers are under no
obligation to view the Internet sites. Reviewers are cautioned that their
anonymity may be compromised when they directly access an Internet site.
Prospective applicants are asked to submit a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities
of other key personnel and participating institutions, and the number and
title of the RFA in response to which the application may be submitted.
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows IC staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent on or before July 18,
2001 to:
Christine Goertz, D.C., Ph.D.
National Center for Complementary
and Alternative Medicine (NCCAM)
National Institutes of Health
6707 Democracy Blvd. Suite 106
Bethesda, MD 20892-5475
(FedEx, UPS or other courier use zip code 20817)
Office (301) 402-1030
Fax (301)480-3621
Goertzc@mail.nih.gov
The research grant application form PHS 398 (rev. 4/98) is
to be used in applying for these grants. These forms are available at most
institutional offices of sponsored research and from the Division of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, email: GrantsInfo@nih.gov.
The RFA label available in the PHS 398 (rev. 4/98)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. Failure to use this label
could result in delayed processing of the application such that it may not
reach the review committee in time for review. In addition, the RFA title
and number must be typed on line 2 of the face page of the application form
and the YES box must be marked.
The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been
modified to allow for this change. Please note this is in pdf format.
Submit a signed, typewritten original of the application,
including the Checklist, and three signed photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the
application must be sent to:
Christine Goertz, D.C., Ph.D.
National Center for Complementary
and Alternative Medicine (NCCAM)
National Institutes of Health
6707 Democracy Blvd. Suite 106
Bethesda, MD 20892-5475
(FedEx, UPS or other courier use zip code 20817)
Office (301) 402-1030
Fax (301)480-3621
Goertzc@mail.nih.gov
Applications must be received on or before the application
receipt date listed in the heading of this RFA. If an application is
received after that date, it will be returned to the applicant without
review. The Center for Scientific Review (CSR) will not accept any
application in response to this RFA that is essentially the same as one
currently pending initial review, unless the applicant withdraws the pending
application. The CSR will not accept any application that is essentially the
same as one already reviewed. This does not preclude the submission of
substantial revisions of applications already reviewed but such applications
must include an introduction addressing the previous critique.
The general instructions provided in PHS-398 must be used
for the preparation of applications except as modified under "Special
Requirements" and as listed below. Because the "Terms and Conditions of
Award" will be included in all awards issued as a result of this RFA, it is
critical that each applicant provides specific plans for responding to the
terms and conditions of award and requirements stated in the RFA. Plans must
take into account NIH staff involvement, as well as how all the
responsibilities of Awardee will be fulfilled. The following items apply to
all applications:
-
General
All applicants should demonstrate their ability to manage a complex trial,
and provide a detailed patient recruitment plan, a detailed data
management plan, and sample size and power calculations. In addition, it
is important to evaluate any side effects or complications of treatment.
-
Trial Organization
The application should describe the organization of the study and how the
trial will be managed. The application should identify the single
applicant organization that will be legally and financially responsible
and accountable for the use and disposition of funds awarded on the basis
of this RFA to other trial sites and institutions participating in the
consortium, and show availability of personnel and facilities capable of
performing and supporting the administrative functions necessary. The
application should provide a plan to assure the maintenance of close
cooperation and effective communication among members of the consortium.
The application should discuss the capability of the applicant
organization and each institution in an applicant consortium to
participate and interact effectively in cooperative, multi-center clinical
trials. The application should discuss the coordination of participating
trial sites, including proposed methods of blinding, communication, data
transfer, and trial oversight (e.g., how will recruitment goals of trial
sites be monitored). A timetable for completion of the various stages of
the trial should be included.
-
Research Design and Data Analysis
The applicant should describe the procedure for assignment of patients to
experimental conditions, as well as the procedures used to assure
compliance with, and standardized implementation of, the proposed
protocol. Applicants should also discuss potential biases in the proposed
research protocol and how they will be addressed. A detailed description,
including a rationale, for of the placebo control selected must be
provided. Clinical (including behavioral), laboratory and physiological
tests and protocols should be described briefly, with additional detail
provided in the appendix if needed. Methods of randomization and
standardization across trial sites should be described and endpoints
clearly defined. The specific criteria and procedures for unblinding
should be specified and justified in the application. Applicants should
discuss patient availability and recruitment. Discuss the characteristics
of the population and the approaches proposed for recruitment, retention
and follow-up. Discuss plans for maintaining the cooperation of the study
population over the length of the trial, including compliance with the
assigned treatment, as well as plans for addressing any anticipated
changes in the composition of the study population over the course of the
trial (e.g., different mortality rates in men versus women). Data should
be presented supporting recruitment and retention estimates.
Describe the methods of data analysis, linking the analyses to the
hypotheses to be tested. Include methods of data preparation and
presentation, analytic methods, and approaches to data synthesis. Discuss
how interim analyses will be handled, as well as comparisons across
subgroups. Data analyses should consider stratification by risk and
protective factors when appropriate. Choice of these factors should be
specified and justified in the application, and incorporated into sample
size calculations. Applications should demonstrate the scientific
expertise required to design, conduct and analyze all proposed adjunct
studies. Such expertise may be provided by a single scientist serving the
entire consortium or more than one such scientist depending upon the
proposed adjunct studies.
-
Women and Minority Subjects
Women and minority individuals should be included in the study population
in accordance with NIH requirements. Specific recruitment targets for
women and minority subjects and plans for achieving these goals must be
explicitly stated in a separate section of the application. Approximate
percentages of women and minority groups expected in the study sample and
the basis for these estimates must be provided. Generally, representation
of women and minorities should occur in the study population in the same
proportions as in the U.S. population having the disease being studied. It
is recognized that this may require oversampling.
-
Budget
All costs required for the proposed trial and adjunct studies should be
included in the application and fully justified. If the trial is designed
for more than a five-year period, complete, justified budgets for the
future years also must be included. The review of the application will
evaluate the entire project. Budgeted costs should include the costs of
clinical research associated with the proposed protocol costs for patient
recruitment and follow-up, adjunct studies, data collection, management
and quality control, and independent on-site quality assurance audits.
Costs at participating trial sites, exclusive of salary, should be
calculated on a per patient-visit. Requested budgets should also include
travel to the Bethesda, Maryland area for two 1-2 day Steering Committee
meetings during the first 12 months, and annually thereafter for the
Principal Investigator, the Trial Manager and up to five trial site Senior
Investigators.
Upon receipt, applications will be reviewed for
completeness by the CSR and responsiveness by the NCCAM. Incomplete and/or
non-responsive applications will be returned to the applicant without
further consideration. Applications that are complete and responsive to the
RFA will be evaluated for scientific and technical merit by an appropriate
peer review group convened by the NCCAM in accordance with the review
criteria stated below. As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the top
half of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the NCCAM and NHLBI
National Advisory Councils.
The goals of NIH-supported research are to advance our
understanding of biological systems, improve the control of disease, and
enhance health. In the written comments reviewers will be asked to discuss
the following aspects of the application in order to judge the likelihood
that the proposed research will have a substantial impact on the pursuit of
these goals. Each of these criteria will be addressed and considered in
assigning the overall score, weighting them as appropriate for each
application. Note that the application does not need to be strong in all
categories to be judged likely to have major scientific impact and thus
deserve a high priority score. For example, an investigator may propose to
carry out important work that by its nature is not innovative but is
essential to move a field forward.
(1) Significance: Does this study address an important
problem? If the aims of the application are achieved, how will scientific
knowledge be advanced? What will be the effect of these studies on the
concepts or methods that drive this field?
(2) Approach: Are the conceptual framework, design,
methods, and analyses adequately developed, well integrated, and appropriate
to the aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics?
-
Overall feasibility and the likelihood of achieving the
clinical trial goals and the potential for a successful trial.
-
Pilot phase experience including evidence of patient
recruitment and retention.
-
Adequacy of the statistical features of the study including
sample size projections and power estimates, methods of analysis, and the
use of sequential analyses of data.
-
Logistical aspects of the project including plans for
patient recruitment, quality control of data, proper randomization and
masking procedures, data collection, data management and reporting, and
plans for defining access and restriction to data. If preliminary data are
not available, the proposal should include a pilot phase to validate these
procedures.
-
Availability of suitable subjects for the clinical trial
and the likelihood of participation through to completion of the study.
-
Adequacy of methods for data collection and reporting from
each consortium institution.
(3) Innovation: Does the project employ novel concepts,
approaches or method? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or technologies?
(4) Investigator: Is the investigator appropriately
trained and well suited to carry out this work? Is the work proposed
appropriate to the experience level of the principal investigator and other
researchers (if any)?
(5) Environment: Does the scientific environment in which
the work will be done contribute to the probability of success? Do the
proposed experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there evidence
of institutional support?
-
Commitment of the consortium institutions and staff to a
collaborative protocol and to the success of the study. The inclusion of
letters of agreement from collaborating investigators, countersigned by
the appropriate institutional official, is necessary. These letters should
state the willingness of the investigators to work with the Steering
Committee and NCCAM staff, and to comply with the policies and procedures
developed by the Steering Committee concerning this trial.
-
Adequacy of the facilities including technical resources
and space.
-
Appropriateness of both the consortium organization and
administration at each trial site.
In addition to the above criteria, in accordance with NIH
policy, all applications will also be reviewed with respect to the
following:
-
The adequacy of plans to include both genders, minorities
and their subgroups, and children as appropriate for the scientific goals
of the research. Plans for the recruitment and retention of subjects will
also be evaluated.
-
A reasonable proposal for study budget and duration in
relation to the research plan.
-
The adequacy of the proposed protection for humans, animals
or the environment, to the extent they may be adversely affected by the
project proposed in the application.
Schedule:
| Letter of Intent Receipt
Date: |
July 18, 2001 |
| Application Receipt Date: |
August 29, 2001 |
| Peer Review Date: |
Oct/Nov, 2001 |
| Council Review: |
January 2002 |
| Earliest Anticipated Start
Date: |
March 1, 2002 |
Award criteria that will be used to make award decisions
include:
-
scientific merit (as determined by peer review)
-
availability of funds
-
programmatic priorities.
Inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or answer questions from potential
applicants is welcome.
Direct inquiries regarding programmatic issues to:
Christine Goertz, D.C., Ph.D.
National Center for Complementary
and Alternative Medicine (NCCAM)
National Institutes of Health
6707 Democracy Blvd. Suite 106
Bethesda, MD 20892-5475
(FedEx, UPS or other courier use zip code 20817)
Office (301) 402-1030
Fax (301)480-3621
Goertzc@mail.nih.gov
Direct inquiries regarding review issues to:
Chief Review Branch
National Center for Complementary
and Alternative Medicine (NCCAM)
National Institutes of Health
6707 Democracy Blvd. Suite 106
Bethesda, MD 20892-5475
(FedEx, UPS or other courier use zip code 20817)
Office (301) 496-4792
Fax (301)480-3621
Direct inquiries regarding fiscal matters to:
Victoria Carper
National Center for Complementary
and Alternative Medicine (NCCAM)
National Institutes of Health
6707 Democracy Blvd. Suite 106
Bethesda, MD 20892-5475
(FedEx, UPS or other courier use zip code 20817)
Office (301) 594-9102
Fax (301)480-3621
This program is described in the Catalog of Federal
Domestic Assistance No. 93.213. Awards are made under authorization of
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241
and 284) and administered under NIH grants policies and Federal Regulations
42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products. In addition, Public Law 103-227, the Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care, health
care, or early childhood development services are provided to children. This
is consistent with the PHS mission to protect and advance the physical and
mental health of the American people.
|
