Release Date:  December 6, 2001

RFA:  RFA-AT-02-003

National Center for Complementary and Alternative Medicine

Letter of Intent Receipt Date:  February 28, 2002
Application Receipt Date:       March 28, 2002



The National Center for Complementary and Alternative Medicine (NCCAM) 
announces the availability of funds to support research into interactions 
between botanical substances and prescription drugs used in the treatment of 
human immunodeficiency virus (HIV) infection and its complications.   
Research findings published in the medical literature suggest harmful 
interactions between botanicals and antiretroviral medications; however some 
reports also suggest beneficial effects from botanical/drug combinations.  
The widespread use of botanicals by persons with HIV-infection and the 
concomitant use of  pharmaceutical drugs pose risks to effective treatment 
for HIV-infection and support the need for this initiative.  In addition, 
reports of beneficial interactions need to be investigated.   This initiative 
is intended to stimulate investigator-initiated biomedical research on 
botanical/drug interactions in vitro, in animal models, and in phase I/II 
clinical studies relevant to the treatment of  HIV-infection and its 
complications.  Research supported by this initiative is expected to prevent 
adverse botanical/drug interactions during therapy for HIV-infection and its 
complications, establish possible synergistic combinations of botanicals with 
pharmaceutical drugs, and increase our knowledge of the mechanisms of action 
of botanicals.  The information developed on interactions between botanical 
substances and pharmaceutical agents used in the treatment of HIV-infection 
and its complications is expected to provide the public and health 
professionals with the information necessary to make appropriate treatment 


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), Botanical/Drug Interactions in HIV, is related to one or 
more of the priority areas. Potential applicants may obtain a copy of 
"Healthy People 2010" at


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 government, and eligible 
agencies of the Federal government. Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 


This RFA will use the National Institutes of Health (NIH) R01 and R21 award 
mechanisms.  Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  This RFA is a one-
time solicitation.  Future revised applications will compete with all 
investigator- initiated applications and be reviewed according to the 
customary peer review procedures. The anticipated award date is September 

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST_IN_TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed  instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001). 
Additional information on Modular Grants can be found at


The NCCAM intends to commit approximately $600,000 total costs in FY 2002 to 
fund one or two R21 and one or two R01 grants in response to this RFA.  An 
R21 applicant may request a project period of up to two years and a budget of 
up to $125,000 direct costs per year.  An R01 applicant may request a project 
period of up to three years and a budget of up to $375,000 direct costs per 
year. The use of modular budgets applies to research grant applications 
requesting up to $250,000 direct costs per year.  Because the nature and 
scope of the research proposed may vary, it is anticipated that the size of 
each award will also vary. Although the financial plans of the NCCAM 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, it is not known if this RFA will be reissued. 


The main objectives of this initiative are to gain information that can help 
to prevent adverse  botanical/drug interactions during therapy for HIV-
infection and its complications, to establish possible synergistic 
combinations of botanicals with pharmaceutical drugs used in treating HIV-
infection and its complications, and to increase our knowledge of the 
mechanisms of action of botanicals.

Complementary and alternative medicine (CAM) practices are described as those 
not presently considered an integral part of conventional medicine.  
Eisenberg et al. estimated that 40% of the general population uses CAM and 
that 18% of individuals taking prescription drugs concurrently use herbs, 
high-dose vitamins, or both.  They estimated that 15 million adults are at 
risk for potential drug-dietary supplement interactions, and that fewer than 
40% of patients surveyed disclosed their CAM use to their physicians.  For 
persons living with HIV/AIDS, estimates of CAM use range from 41% to 84%, 
with 21% to 27% of participants in various surveys reporting the use of herbs 
in addition to antiretroviral medication.  In several surveys, only 43% to 
67% of  persons living with HIV/AIDS reported that their doctors were aware 
of their CAM use and in  one study, 25% of patients reported that the 
prescribing physician was unaware of their CAM use at all.  At the same time, 
increasing numbers of physicians are referring patients to CAM providers or 
prescribing CAM interventions themselves.  The frequency and extent of 
adverse drug reactions, or even positive effects due to concurrent use is 
unknown.  Given the complex pharmaceutical regimens of antiretroviral therapy 
and the large numbers of patients who are taking both botanicals and 
antiretrovirals or other medications to treat complications, the risk of 
interactions may be substantial.  

Interactions between botanicals and drugs may be classified as 
pharmacokinetic or pharmacodynamic.  Pharmacokinetic interactions result in a 
change in the amount of available drug through an effect on the absorption, 
transport, distribution, metabolism or excretion of the drug.  
Pharmacodynamic interactions alter the pharmacologic effect of the drug and 
may be inhibitory, additive, or synergistic.  P-glycoprotein, important to 
cellular transport, and the cytochrome P450 enzyme system have significant 
roles in the metabolism of HIV medications.  P-glycoprotein's action in 
intestinal cell wall, hepatocytes, and renal tubular cells affects drug 
absorption and excretion in bile and urine.  The cytochrome P450 system 
contains several families of isoenzymes with the most important for 
antiretroviral drug metabolism being 3A4 (CYP3A4).  The cytochrome enzyme 
system metabolizes most of the pharmaceuticals currently used in the 
treatment of HIV and many of the investigational drugs in development, as 
well as being an important pathway for the metabolism of certain botanical 

Recent research regarding interaction between herbs and pharmaceuticals used 
to treat HIV-infection demonstrate the real dangers of combining herbal 
therapies with antiretroviral therapy.  In a study with healthy volunteers, 
St. John's wort decreased blood levels of the protease inhibitor indinavir to 
levels that in patients on therapy for HIV-infection could lead to treatment 
failure.  St. John's wort is known to induce CYP3A4 for which protease 
inhibitors are substrates.  A separate study demonstrated an interaction 
between garlic and another protease inhibitor, saquinavir, that is known to 
be a substrate for CYP3A4.  Healthy volunteers were given saquinavir alone 
followed by garlic tablets in doses equivalent to culinary amounts of garlic.  
Garlic lowered the blood levels of saquinavir not only while it was being 
taken, but also after a washout period.  In vitro studies of the effect of 
garlic on CYP3A4 yield conflicting results – some inducing and some 
suppressing activity of CYP3A4.  The exact mechanism of this interaction is 
not known and may be due to the induction of CYP3A4 or P-glycoprotein.  This 
herb/drug interaction also poses the risk of treatment failure in patients on 
therapy for HIV, even if they are only eating garlic.  Since Milk thistle, 
ginseng, and skullcap are known to affect CYP450 metabolism in vitro, they 
also may interact with medications used to treat HIV-infection.  

In addition, the possibility of botanical/drug interactions having beneficial 
effects on the treatment of HIV-infection should be investigated.  In a 
clinical study, use of a mushroom extract enhanced the effect of ddI.  Also, 
an anecdotal report in an HIV community newspaper claims benefit from the use 
of olive leaf extract in combination with 3TC.  Research is needed to 
understand better the documented and potential interactions, as well as to 
identify additional herb/drug combinations that may pose risks or offer 
benefits.  The award of research grants through this program will permit 
exploration of the range of possible interactions. 


The proposed initiative is expected to stimulate investigator-initiated 
biomedical research on botanical/drug interactions in vitro, in animal 
models, and in phase I/II or case control clinical studies. The phase I/II 
clinical studies are expected to examine the pharmacokinetics or 
pharmacodynamics of the botanical/drug combination in contrast to these 
parameters when the botanical or drug is administered alone. This RFA invites 
proposals designed to explore the cellular and molecular effects of botanical 
interactions with proprietary drugs, or studies which may help to predict the 
effects of the botanicals on drug action and metabolism in vivo.  Case 
control studies should be aimed at elucidating the relationship between a 
botanical product and specific events (adverse or beneficial) in the presence 
of a proprietary drug.  Studies may include biomarkers such as CD4 counts or 
viral loads as secondary outcome measures.


The NCCAM does not usually accept research applications in the botanical 
category that focus on the isolation of active ingredients from herbal 
preparations, except when this is necessary for identification and 
standardization of optimal whole products, when comparisons are being made to 
the complex product, or to investigate metabolic pathways and mechanisms of 
action as part of the proposed research project. Therefore, conventional drug 
discovery and drug development approaches using botanicals as the source are 
not considered to be within the scope of this RFA.  It is the responsibility 
of the applicant to document the characterization, standardization, and 
quality control of the botanical products chosen.  Research projects can be 
basic (mechanistic) or clinical studies other than Phase III trials.  For the 
purpose of this RFA, a Phase III trial is defined as a broadly based 
prospective investigation usually involving a substantial number of human 
subjects either at a single site or at multiple sites.  The primary objective 
of such trials is to evaluate an experimental intervention in comparison with 
a standard or control intervention, or to compare two or more existing 
treatments.  In Phase III trials, the primary endpoint is usually a 
significant change in an identified clinical outcome.  The definition 
includes interventions given for disease prevention, prophylaxis, diagnosis, 
or therapy.  Research components involving phase I and II clinical trials 
must include provisions for assessment of patient eligibility and status, 
rigorous data management, quality assurance, and auditing procedures. 

NIH policy requires data and safety monitoring for all clinical trials with 
the method and degree of monitoring being commensurate with the risks (NIH 
Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, 
June 12, 1998:  
The NIH has also released "Further Guidance On A Data And Safety 
Monitoring For Phase I and Phase II Trials", NIH Guide, June 5, 2000:  In 
addition, NCCAM requires that all masked clinical trials, regardless of size, 
establish an independent data and safety monitoring board.  The Data Safety 
Monitoring Guidelines for NCCAM-supported clinical trials are available at:  Funds should 
be budgeted for these activities.  They should not duplicate internal review 
and monitoring systems that are already in place at the institution. 

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 clinical research 
projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
a complete copy of the updated Guidelines are available at  
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398; and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  For R01 applications, the limit for Items a-d in 
the Research Plan is 25 pages, while R21 applications have a limit of 15 
pages.  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.


The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at:

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.


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 this RFA.  
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 NCCAM staff to estimate the potential review workload and 
plan the review. 

Mail/Fax letters of intent on or before February 28, 2002 to: 

Morgan N. Jackson, M.D., M.P.H.
National Center for Complementary and Alternative Medicine 
National Institutes of Health
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Telephone:  (301) 402-1278
FAX:  (301) 480-3621 


The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format. For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.


o The purpose of the NCCAM's Exploratory/Developmental Research (R21) grant 
mechanism is to provide investigators, at all career levels, with a funding 
opportunity for exploring the feasibility, as well as the development, of 
projects investigating botanical/drug interactions in HIV.  The R21 mechanism 
is specifically intended to support innovative ideas where preliminary data, 
as evidence of feasibility, are sparse or do not exist.  These grants are not 
intended for large-scale undertakings or to support or supplement ongoing 
research.  Rather, R21-supported projects are intended to serve as a basis 
for planning and strengthening future investigator-initiated research project 
grant applications (R01).  It is important to note that, while originality of 
approach and potential significance of the proposed research are major 
considerations in evaluation for funding R21 grants, the applicant is also 
responsible for presenting the background literature that provides some basis 
for the approach and developing a rigorous research plan. 

o For R21 applications, Direct Costs are limited to a maximum of $125,000 per 
year for a maximum of two years.  Direct Costs requested for the proposed 
period may not exceed $250,000.  Direct costs should be requested in 
increments of $25,000 (Modular Budget).  Total Costs should equal the modular 
Direct Costs plus Facilities and Administrative (F&A) costs.  The award is 
nonrenewable and may not be used to supplement an ongoing project. 

o Do not exceed a total of fifteen pages for Items a-d in the Research Plan.  
Tables and figures are included in the page limitation.  Applications that 
exceed the page limitation or NIH requirements for type size and margins 
(refer to PHS 398 application for details) will be returned to the applicant 
without further consideration.  The fifteen-page limitation does not include 
Items e-i (Human Subjects, Vertebrate Animals, Literature Cited, Consortia, 
and Consultants). 

o Color illustrations or original photographs may be included in an Appendix.  
These are allowed only if there are copies of black and white figures 
appearing in the body of the application.  No other appendix material is 

o Applications not following the above instructions will be returned to the 
applicant without review. 

The RFA label available in the PHS 398 (rev. 5/2001) 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 RFA label is also available at:

Submit a typewritten, signed original of the application, including the 
Checklist, and three signed photocopies, in one package to: 

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: 

Dr. Martin Goldrosen
Director, Scientific Review Branch
National Center for Complementary and Alternative Medicine 
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Telephone:  (301) 594-2014 
FAX:  (301) 480-2419 

Applications must be received by March 28, 2002.  If an application is 
received after that date, it will be returned to the applicant without 

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. 


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by  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 may 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 National Advisory Council. 

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? 

(3) Innovation: Does the project employ novel concepts, approaches or 
methods?  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 

Because the exploratory grant mechanism (R21) is designed to support 
innovative ideas, preliminary data as evidence of feasibility of the project 
are not required.  However, the applicant does have the responsibility for 
developing a sound research plan approach, including appropriate statistical 
analyses and sample size calculations where appropriate.  Innovation of the 
project and potential significance of the proposed research will be major 
considerations in the evaluation of this mechanism. 

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 

o The reasonableness of the proposed budget and duration in relation to the 
proposed research. 

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. 

Letter of Intent Receipt Date:    February 28, 2002
Application Receipt Date:         March 28, 2002
Council Review:                   August 2002
Earliest Anticipated Start Date:  September 2002

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 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: 

Morgan N. Jackson, M.D., M.P.H. 
National Center for Complementary and Alternative Medicine 
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475 
Telephone:  (301) 402-1278 
FAX:  (301) 480-3621 

Direct inquiries regarding review issues to: 

Dr. Martin Goldrosen 
Director, Scientific Review Branch
National Center for Complementary and Alternative Medicine 
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Telephone:  (301) 594-2014 
FAX:  (301) 480-2419 

Direct inquiries regarding fiscal matters to: 

Mrs. Victoria Carper
Grants Management Officer
National Center for Complementary and Alternative Medicine
National Institutes of Health 
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Phone:  301-594-9102 
Fax:  301-480-3621 


This program is described in the Catalog of Federal Domestic Assistance No. 
93.213. Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review. The 
PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products. In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children. This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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