ANCILLARY STUDIES ON CONTROL GROUPS IN CLINICAL TRIALS

RELEASE DATE:  April 3, 2002

PA NUMBER:  PA-02-094

EXPIRATION DATE: February 2, 2005, unless reissued.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)        
 (http://www.niddk.nih.gov/)

National Center for Complementary and Alternative Medicine (NCCAM)
 (http://www.nccam.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) and the National Center for Complementary and Alternative 
Medicine (NCCAM) invites grant applications for ancillary studies to 
NIH funded interventional clinical trials to address the biological, 
behavioral and statistical issues related to the control or comparison 
group used in these trials and the effects of inclusion of a placebo 
group on clinical trial design..  The NIDDK/NCCAM cosponsored workshop 
"The Science of the Placebo: Toward an Interdisciplinary Research 
Agenda"(http://placebo.nih.gov), held November 19-21, 2000 on the NIH 
campus emphasized that the use of placebos as controls in research 
designed to assess the efficacy of therapeutic or preventive agents is 
a complex issue.

Applications are sought which utilize the patient populations in 
existing or planned NIH clinical trials to address key unresolved 
questions in clinical trial design about the control group. 
Applications responsive to this solicitation would examine such 
questions as: the magnitude of placebo effects on various types of 
outcome measures and at various times after initiation of the 
intervention; the assessment by potential trial participants or 
referring physicians of benefits and risks of trial participation; the 
impact of placebo and active control groups on recruitment; the 
effectiveness of blinding and the perception of patients and/or 
investigators on trial group membership and correlation with effect. 
 
RESEARCH OBJECTIVES

Background:  A control group receiving placebo treatment is often used 
in clinical trials to assess the efficacy of the study intervention.  
This use of placebo controls has raised a number of ethical, 
philosophical, statistical and trial design issues.  Many of these 
issues were highlighted at the National Institutes of Health workshop 
"Science of the Placebo: Towards and Interdisciplinary Research Agenda" 
held in November 2000 (http://placebo.nih.gov).  

There is broad unanimity in the principle that in the conduct of 
clinical trials the inclusion of a placebo group is compatible with 
equipoise when there is no established treatment available.  
Implementation of this principle, however, requires complex judgments 
of benefit and risk about which there is frequently not general 
agreement.  A more rigorous basis is needed to inform the selection of 
the appropriate control group in clinical trials.

Objectives:  The purpose of this PA is to fund studies which will 
utilize the patient populations in existing NIH funded clinical trials 
to address the numerous issues and unresolved questions in clinical 
trial design which are involved in selecting and using a control group 
in clinical trials.  Appropriate topics for investigation would 
include, but are not limited to:

- studies to determine how potential participants and referring 
physicians approach risk/benefit assessment;

- studies which address the anticipated impact of the magnitude of the 
placebo effect  on trial design at various time points and with various 
study instruments; 

- the use of control groups in surgical interventions;

- the magnitude of the placebo effect in various diseases;

- the relationship between the size of the placebo effect and outcome 
measures, especially those which use patient self report of response to 
therapy;

- the relationship between placebo effect and regression to the mean;

- the duration of the placebo effect;

- patient factors that are predictive of the magnitude of the placebo 
effect;

-the effectiveness of blinding and the perception of patients and/or 
investigators on trial group membership and correlation with effects;

-studies to determine the most effective placebo and comparison arms in 
clinical trials that are evaluating the efficacy of complex systems of 
medicine, holistic therapies, or complementary and alternative medicine 
(CAM) modalities such as chiropractic and acupuncture.

It is anticipated that the results of the studies funded through this 
PA will provide new insights into the role of the placebo and control 
group in clinical trials and will provide better methods for trial 
design and analysis.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research 
project grant (R01) award and the exploratory/developmental grant (R21) 
mechanism.  The purpose of the R21 award mechanism is to demonstrate 
feasibility and obtain preliminary data.  These grants will not be 
renewable; continuation of these projects will be through the regular 
research grant (R01) mechanism. Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of 
the applicant.  The total project period for an application submitted 
in response to this PA may not exceed five years for R01 projects and 
two years for R21 projects.  R21 applications cannot exceed $125,000 in 
direct costs per year. R01s greater that $250,000 per year require 
detailed budgets.  

This PA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.

Ancillary studies to both U01, R01, and P50 (NCCAM only) funded trials 
will be accepted.  Ancillary studies to trials funded as U01s will 
require written approval by the institute Program Officer.  Studies for 
trials funded as R01s and P50s will require written approval from the 
Principal Investigator of the trial.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs. 

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the 
opportunity answer questions from potential applicants.  Inquiries may 
fall into three areas:  scientific/research, peer review, and financial 
or grants management issues:

o Direct your questions about scientific/research issues to:

for NIDDK:

Leroy M. Nyberg, Jr., Ph.D., M.D. 
Division of Kidney, Urologic, and Hematologic Diseases
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 627 MSC-5458 
Bethesda, MD 20892-5458
Telephone:  (301) 594-7717
FAX: 301-480-3510
E-mail:  ln10f@nih.gov

for NCCAM:

Nancy J. Pearson, Ph.D.
Program Officer
National Center for Complementary 
  and Alternative Medicine
6707 Democracy Blvd, Room 106, MSC-5475
Bethesda, MD  20892-5475
Telephone:  (301) 594-0519
Fax:  (301) 480-3621
E-mail:  pearsonn@mail.nih.gov

o Direct inquiries about financial or grants management matters to:

NIDDK:

Trude Hilliard
Grants Management Branch
Division of Extramural Activities 
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 717, MSC 5456
Bethesda, MD 20892
Telephone:  (301) 594-8859
Fax:  (301) 480-3504
E-mail:  th105x@nih.gov

NCCAM:

Victoria Carper
Grants Management Officer
National Center for Complementary and Alternative Medicine
6707 Democracy Blvd, Rm 106, MSC-5475
Bethesda, MD  20892
Telephone: 301 594 9102
FAX: 301 480 3621
Email: carperv@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at http://grants.nih.gov/grants/dates.htm.  
Application deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS:  All application 
instructions outlined in the PHS 398 application kit are to be 
followed, with the following requirements for R21 applications:  

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the 
total direct costs limit of $100,000 per year. 

2. Although preliminary data are not required for an R21 application, 
they may be included.

3.  Sections a-d of the Research Plan of the R21 application may not 
exceed 15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to 
circumvent the page limit for the research plan. Copies of appendix 
material will only be provided to the primary reviewers of the 
application and  will not be reproduced for wider distribution. The 
following materials may be included in the appendix:

Up to five publications directly relevant to the project. Surveys, 
questionnaires, data collection instruments, and clinical Protocols.  
These may be stapled as sets.

Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included 
within the 15 page limit of items a-d of the research plan

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

Applicants must define, in their application, the specific clinical 
trial by grant number(s), trial title, and Principal Investigator 
and/or Steering Committee Chairperson, for which they are proposing an 
ancillary study.  They must also include in the application a signed 
letter from either the Program Officer (for U01 clinical trials) or the 
Principal Investigator approving the concept and cooperation in the 
study.

Applicants must include in the appendix to the application copies of 
the relevant grant or clinical trial protocol, so that reviewers can 
understand the context of the proposed study.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR:  Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of NIH institutes or centers who has agreed to accept 
assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR 
will not accept any application in response to this PA 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 a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
score
o Receive a second level review by the appropriate national advisory 
council or board
 
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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you 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 your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a program announcement will 
compete for available funds with all other recommended applications.  
The following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priority.

REQUIRED FEDERAL CITATIONS

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20
01.htm.  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 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA 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.

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.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

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 PA 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.

This program is described in the Catalog of Federal Domestic Assistance 
No. 93. 93.849 and 93.213 Awards are under authorization of the Public 
Health Service Act, Title IV, Part A (Public Law 78-410, as amended by 
Public Law 99-158, 42 USC 241 and 285) 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 and contract 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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