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
[email protected]

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: 
[email protected].

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
[email protected]

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
[email protected]

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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