EDTA CHELATION THERAPY FOR CORONARY ARTERY DISEASE
Release Date: April 30, 2001
RFA: RFA-AT-01-004
National Center for Complementary and Alternative Medicine
(http://nccam.nih.gov)
National Heart Lung and Blood Institute
Letter of Intent Receipt Date: July 18, 2001
Application Receipt Date: August 29, 2001
PURPOSE
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.
HEALTHY PEOPLE 2010
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/.
ELIGIBILITY REQUIREMENTS
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.
MECHANISM OF SUPPORT
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.
FUNDS AVAILABLE
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.
RESEARCH OBJECTIVES
Background
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 Therapy
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).
Pharmacology of EDTA
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.
Possible Mechanisms of Action of EDTA
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.
Studies of EDTA Chelation Therapy in Arteriosclerosis
Coronary Artery Disease
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.
Peripheral Vascular Disease
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).
Cerebrovascular Disease
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.
Developments in the Assessment of EDTA Chelation Therapy for Arteriosclerosis
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:
o Development of control/comparison groups that are appropriate for this
project.
o Determination of the efficacy of EDTA chelation therapy in treating CAD on
average and in various sub-populations.
o Determination of the safety of EDTA chelation therapy.
o Use of assays to determine metabolic changes in human subjects that may
provide information on the potential mechanisms of action of EDTA chelation
therapy.
Research Plan
1. 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.
2. 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:
1) general health status/quality-of-life indicators,
2) 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
3) health care utilization (e.g., increased or decreased use of other
medications or office visits, cost-effectiveness data).
3. 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.
4. Compliance
Research designs that maximize patient compliance should be described and
justified in the application.
5. 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.
6. 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.
SPECIAL REQUIREMENTS
Study Organization
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:
1. 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.
2. 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.
4. 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.
5. 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.
6. Data Coordination, Management and Quality Control
Applicants should document their previous experience and must present:
a) a plan for randomization, data coordination, data collection and management
across trial sites,
b) 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,
c) a plan describing development of appropriate placebo control group(s),
d) a description of the proposed intervention(s) and outcome measures,
e) methods for monitoring the quality and consistency of the intervention and
outcome measures,
f) protocols for data collection, formatting and transmission to and from
individual trial sites, prototypes of data collection forms should be included
in an appendix,
g) a comprehensive set of procedures to assure data quality and also
procedures to assure confidentiality of subjects,
h) a plan for training programs to educate staff at trial sites about
operating procedures with the goal of maximizing efficiency of data
operations,
i) data quality control systems,
In addition, the applicants should provide evidence of their prior management
capability to:
a) estimate appropriate and reasonable resources needed for the EDTA chelation
trial,
b) manage resources efficiently during the research,
c) adjust assigned resources to changing demands as the research work
progresses,
d) keep NCCAM informed of changes of resource allocations, and
e) subcontract with affiliated trial sites or other outside organizations.
7. 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.
8. 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.
TERMS AND CONDITIONS OF THE AWARD
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.
A. 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:
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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:
a. 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.
b. 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.
B. NIH Staff Responsibilities
1. Normal Stewardship
a) 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.
b) 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.
c) 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.
d) 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:
1) failure to implement the final collaborative protocol in a timely fashion,
2) substantive changes in the agreed-upon protocol to which the NCCAM does not
agree,
3) substantial shortfall in participant recruitment, follow-up, data
reporting, quality control, or other major breech of the protocol,
4) emergence of new information that diminishes the scientific importance of
the study question,
5) patient safety and regulatory concerns,
6) accrual goals met early and,
7) study results that are already conclusive.
e) 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.
f) 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).
2. Substantial Additional Involvement
a) 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.
b) 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.
c) 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.
C. Collaborative Responsibilities
1. 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:
1) assessment of protocol adherence, treatment administration, and measurement
of outcomes,
2) tracking and reporting of patient accrual and adherence to defined accrual
goals,
3) ongoing assessment of case eligibility and availability,
4) timely medical review and assessment of patient data,
5) rapid reporting of morbidity, and measures to ensure communication of this
information to all interested parties,
6) interim evaluation and consideration of measures of outcome as consistent
with patient safety and good clinical trials practice,
7) timely communication of study results to NCCAM, the scientific community
and the U.S. Public, and
8) 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.
3. 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.
4. 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:
1. 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,
2. Identify problems relating to safety over the course of the study,
3. Identify needs for additional data relevant to safety issues and request
these data from the study investigators,
4. Review unmasked outcome data as needed and appropriate over the course of
the trial,
5. Propose appropriate analyses and periodically review developing data on
safety and endpoints,
6. 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.
7. 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.
8. 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.
D. 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 D.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
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.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
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.
LETTER OF INTENT
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
APPLICATION PROCEDURES
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 301/710-0267, 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.
Preparation of the Application
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:
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
REVIEW CONSIDERATIONS
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.
Review Criteria
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?
o Overall feasibility and the likelihood of achieving the clinical trial
goals and the potential for a successful trial.
o Pilot phase experience including evidence of patient recruitment and
retention.
o 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.
o 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.
o Availability of suitable subjects for the clinical trial and the likelihood
of participation through to completion of the study.
o 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?
o 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.
o Adequacy of the facilities including technical resources and space.
o 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:
o 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.
o A reasonable proposal for study budget and duration in relation to the
research plan.
o 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
Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities.
INQUIRIES
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
AUTHORITY AND REGULATIONS
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.
References cited in this RFA can be obtained at http://nccam.nih.gov
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