Subject: NIH GUIDE - Vol. 20, No. 10, March 8, 1991 - RFA HD9102
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 08 Mar 91 09:05 EST

Hi Paul,
   Please post this one to the listserver as: RFAHD-91-02.910308
     Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA HD9102 HD-91-02 P1O1 *****************************************
 
EVENT RECORDINGS OF HIGH RISK INFANTS ON APNEA MONITORS
 
RFA:  HD-91-02
 
P.T. 34; K.W. 0765035, 0706020, 0403020, 1004008
 
National Institute of Child Health and Human Development
 
Application Receipt Date:  June 10, 1991
 
PURPOSE
 
The National Institute of Child Health and Human Development
(NICHD) invites applications from clinical investigators
willing to participate with NICHD under several Cooperative
Agreements to perform a multi-center collaborative study
regarding the usefulness of home monitors in the management
of infantile apnea.
 
The NICHD intends to assist investigators to establish a
network of clinical trial sites, with central data analysis,
and data management which will evaluate home apnea
monitoring in high risk infants.  The specific aims of the
study conducted in response to this solicitation are to
improve the quality of home monitoring, determine compliance
in monitor use, and obtain physiologic parameters of
cardiorespiratory episodes in infants at risk for life-
threatening events.  These specific aims can now be achieved
with the availability of event recording technology in the
home.
 
The goals of the study are to (1) determine the frequency,
duration, and type of respiratory and cardiac alterations in
infants at risk for a life-threatening event, that are
recorded with available state of the art technology
preceding, during, and following an alarm event, (2)
determine the compliance with home monitoring in this
population, and (3) obtain information on the physiologic
and clinical significance of recorded alarm events.
 
The Public Health Service is committed to achieving the
health promotion and disease prevention objectives of
Healthy People 2000, a PHS-led national activity.  This
Request for Applications (RFA), "Event Recordings of High
Risk Infants on Apnea Monitors," is related to the priority
area of "Maternal and Infant Health."
Potential applicants may obtain a copy of "Healthy People 2000"
(Full Report:  Stock No. 017-001-00474-0) or "Healthy People 2000"
(Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office,
Washington, D.C. 20402-9325 (telephone 202-783-3238).
 
BACKGROUND
 
Each year between 6,000 and 7,000 infants in the United
States die with a diagnosis of Sudden Infant Death Syndrome
(SIDS).  SIDS is defined as the "sudden death of an infant
under one year of age which remains unexplained after a
thorough case investigation, including performance of a
complete autopsy, examination of the death scene, and review
of the clinical history" (1). Despite success in reducing
infant mortality overall, the incidence of SIDS has changed
little, and with an annual rate of 1-2 deaths per 1000 live
births, it is the leading cause of post-neonatal mortality
in the United States.
 
Efforts to prevent SIDS deaths are hampered by an inability
to identify infants at risk prior to the event, the
inadequate knowledge regarding the physiological processes
leading to its occurrence, or to the terminal event.  The
most compelling hypotheses regarding the pathophysiology of
SIDS suggest that infants that eventually die suddenly have
abnormalities in cardiorespiratory control which may have
their origins in fetal life, and that the infants die of
primary cardiac or respiratory failure.  Analyses of
respiratory and cardiac function during sleep have shown
that infants who later died of SIDS have higher heart rates
and diminished variability in the respiratory associated
heart rate variability within the first postnatal week (2) .
In other studies, increased incidence and frequency of mixed
and obstructive apnea during sleep were observed in
prospective polysomnographic recordings of SIDS victims
compared with control infants (3,4).
 
The majority of SIDS victims cannot be diagnosed as being at
risk prior to the lethal event.  In order to conduct an
investigation of whether infantile apnea monitors are
obtaining appropriate data to describe life-threatening
events, a subpopulation of infants who have been identified
as "at risk" must be studied.  These infants, for whom home
monitoring of respiration and heart rate is medically
indicated, include: premature infants who have apnea at time
of discharge from hospital, infants who have experienced a
severe apparent life-threatening event (ALTE), subsequent
siblings of SIDS victims, and infants with bronchopulmonary
dysplasia (BPD).
 
ALTE:  ALTE describes a clinical syndrome with a variety of
causes.  It is defined as an episode that is frightening to
the observer and is characterized by some kind of apnea,
color and muscle tone changes, choking or gasping (5).
Infants who have an unexplained cessation of breathing and
who are greater than 37 weeks gestation are referred to as
having "apnea of infancy."  Such infants without a treatable
cause of ALTE are monitored at home. The reported incidence
of death in this population ranges from 0-6 percent, and in infants
having a severe episode requiring resuscitation, it ranges
between 10 and 25 percent (5,6).
 
Siblings of SIDS victims:  Subsequent siblings of SIDS
victims are thought to be at a 2-10 fold increased risk for
SIDS.  Because of the comfort that monitoring provides to
parents of previous SIDS victims, monitoring has been
recommended for siblings of two or more SIDS victims.
 
Premature infants:  Infants who have "apnea of prematurity"
are at increased risk for SIDS by virtue of their
immaturity.  Approximately 18 percent of SIDS victims are premature
infants, with the risk for SIDS increasing with decreasing
birthweight (7).  It has been reported that the incidence of
death after discharge from hospital in premature infants
with BPD is as high as 11 percent.
 
In the last decade, the population of infants surviving the
neonatal period is increasing, and includes a larger number
of very low birthweight infants, infants with BPD, and
infants of substance abusing mothers.  As a group, they have
an increased incidence of apnea after discharge from the
Neonatal Intensive Care Network (NICU).  The usefulness of
home monitoring to evaluate and manage infants with apnea or
experiencing an ALTE must be determined.
 
Although as many as 40,000-45,000 monitors are in use in the
United States at a given time (5), no prospective controlled
clinical trials have been conducted to assess the efficacy
of home monitoring to prevent deaths either in symptomatic
or asymptomatic high risk populations.  Data from a
retrospective study showed similar rates of SIDS in
monitored and unmonitored infants referred for evaluation to
a monitoring program.  These infants were subsequent
siblings of SIDS victims, premature infants with apnea, or
infants experiencing an ALTE (8). However, in order to
interpret the mortality rates in monitoring programs, and
the usefulness of monitoring in managing high risk infants,
information is needed on compliance, the reliability of
alarms as measuring true events, and the causes of death.
 
Among identified problems of monitor use are compliance
issues.  Investigation of nine SIDS deaths among patients
referred to an evaluation and monitoring program in 1984 and
1985 revealed that non-compliance with monitor use was 60 percent
at the time of death and in only one case was it determined
that the monitor was used properly (9). This high non-
compliance rate has been observed in other programs (10) and
has been attributed to particular sociodemographic
characteristics of the monitored population.
 
A second problem is the incidence of false alarms.  Two
studies of documented monitoring have revealed that the
majority of alarms in the home are not true
cardiorespiratory events.  In one cohort, 55 percent of the episodes
which triggered that alarm were due to mechanical
malfunction, 19 percent to shallow breathing, and 6 percent could not be
determined or were due to a combination of loose leads and
insignificant respiratory pauses (10).
 
The second study of 14,131 recorded episodes found that 23 percent
were false alarms, i.e., visual inspection of the record did
not verify apnea or bradycardia, 69 percent were due to movement or
loose leads and only 8 percent represented true apnea or
bradycardia (11).  Documented monitoring was used to improve
the management of patients by providing parents with the
information that their infants were not having true events
and monitor use could be discontinued, or by changing the
monitoring parameters and educating parents on appropriate
monitor use.  Almost half of the true events occurred in
infants who were asymptomatic at the time of monitoring,
raising the question of the physiologic significance of
apnea and bradycardia as they are currently defined.
 
The studies which demonstrate the value of recording
episodes detected by home monitors should be extended to a
larger population with long term observation and follow-up,
and investigation of sudden deaths.  A study conducted in
this manner may identify clinical markers for infants at
risk for severe ALTE or SIDS, and provide guidelines for the
appropriate management of infants and parents using home
monitors.
 
If oxygenation is also measured and correlated with
respiratory and cardiac parameters, we may gain information
on the physiologic significance of repeated occurrences of
prolonged apnea, on the relationship of desaturation to
bradycardia, and on an infant's repertoire for recovery.
 
1.   NICHD Workshop: Sudden Infant Death Syndrome
Definition, June 20, 1989; Zylke JW.  JAMA 262: 1565- 1566,
1989.
 
2.  Kluge KA, Harper RM, Schechtman VL, Wilson AJ, Hoffman
HJ, Southall DP. Pediatr Res 24: 677- 682, 1988.
 
3.  Steinschneider A, Weinstein SL, Diamond E.  Pediatrics
70: 858- 863, 1982.
 
4.  Kahn A, Blum D, Rebuffat E, Sottiaux M, Levitt J,
Bochner A, Alexander M, Grosswasser J, Muller MF.
Pediatrics 82: 721- 727, 1988.
 
5.  National Institutes of Health Consensus Development
Conference on Infantile Apnea and Home Monitoring, 1986.
Pediatrics 79: 292- 299, 1987.
 
6.  Oren J, Kelly D, Shannon DC.  Pediatrics 77: 495- 499,
1986.
 
7.  Hoffman HJ, Damus K, Hillman L, Krongrad E.  Annals NY
Acad Sci 533: 13- 30, 1988.
 
8.  Davidson Ward SL, Keens TG, Chan LS, Deming DD, Martin
GI, Nickerson BG, vanderHal AL.  Pediatrics 77: 451- 458,
1986.
 
9.  Meny RG, Blackmon L, Fleischmann D, Gutberlet R,
Naumberg E.  AJDC 142: 1037- 1040, 1988.
 
10.  Nathanson I, O'Donnell J, Commins MF.  AJDC 143: 476-
480, 1989.
 
11.  Weese-Mayer D, Brouillette RT, Morrow AS, Conway LP,
Klemka-Walden LM, Hunt CE.  J Pediatr 115: 702- 708, 1989.
 
STUDY ORGANIZATION AND SCOPE
 
The NICHD will establish a network of approximately five
clinical units and a Data Coordinating and Analysis Center
which will develop and conduct a standard, common protocol.
The specific responsibilities are as follows: (1) the
clinical units will have primary responsibility for
enrollment and evaluation of study participants; (2) one of
the clinical units will serve as resource for the clinical
centers and will be termed the Clinical Trial Operations
Center.  It will be responsible for supporting the sites
regarding protocol implementation, and for the
initial step in central data collection, and  (3) the Data
Coordinating and Analysis Center will have responsibility
for data management and analysis.  A multi-center network is
necessary to enroll a large number of high risk infants in a
reasonable time period and to ensure that the enrolled
patient populations reflect national demographics and
clinical management of high risk infants.
 
NICHD invites applications from competent, experienced
investigators who meet the following minimum standards:
 
NOTE:  An Institution may apply to be a Clinical Unit, and
if qualified, to be the Clinical Trial Operations Center in
the same application. Institutions applying to be a Clinical
Unit are not barred from applying to be The Data
Coordinating and Analysis Center provided that independence
of functions is demonstrated. Therefore, a separate
application is required  for the Data Coordinating and
Analysis Center.  Institutions applying to be the Clinical
Trial Operations Center may not apply to be the Data
Coordinating and Analysis Center.  An Institution may apply
to be the Data Coordinating and Analysis Center only.
 
o  Standards for Clinical Unit Applicants
 
1.  Participants must be based at a pediatric pulmonology
unit or a neonatology program with appropriate follow-up
and/or sleep laboratory.
 
2.  Applicants must have a history of successful clinical
research, and expertise in research design.
 
3.  The unit and applicants must have experience with
monitoring high risk infants. Experience should be
demonstrated as follows:
 
o  Established programs to identify high risk infants
   through appropriate clinical evaluations.  These include
   polysomnographic recordings, neurologic assessments, and
   other clinical evaluations to detect defined causes of
   apnea or ALTE.
 
o  Established programs and staff to manage and follow these
   infants on an inpatient and outpatient basis, to include
   home monitoring, through the first year of life.
 
o  Established programs to support the families of infants
   on home monitors.
 
o  Experience with the most current home apnea monitoring
   and recording technologies.
 
o  Expertise to analyze event recordings of respiratory,
   cardiac, and oxygenation parameters.
 
4.  Applicant units should have available patients in each
high-risk category: premature infants with pathologic apnea,
infants presenting with an ALTE, and siblings of SIDS
victims.  Although they are at risk for cardiorespiratory
events and death, infants with significant lung disease i.e.
requiring oxygen at discharge, and infants with congenital
disorders of respiratory or cardiac function and congenital
disorders do not meet the criteria for SIDS risk.
 
5.  The applicant unit should have as collaborators or
consultants, physicians with expertise in pediatric
neurology, cardiology, infectious disease and immunology,
gastroenterology, pulmonology.
 
6.  An experienced research nurse and/or NICU nurse must be
among the key personnel.
 
7.  The applicant unit should have facilities to conduct the
clinical and laboratory components of the study including
polysomnography, hematology, chemistry, microbiology,
infectious disease and immunology.
 
8.  The applicant should have collaborators or consultants
with expertise in pediatric pathology and should make
provision for autopsy and death scene investigation by
qualified pathology and forensic personnel for all infants
enrolled in the study who die suddenly in the first year of
life.   These personnel will be expected to follow a
standard autopsy and death scene investigation protocol
which will be developed as part of the study protocol.
 
9.  The Principal Investigator and staff must be prepared to
participate in a cooperative manner with other clinical
centers, the Data Coordinating and Analysis Center, and
NICHD in the development and implementation of the study
protocol, manuals, data forms, and data management.
 
10.  The applicant must exhibit a preparedness to pursue
capitation of particular operational costs of the protocol
(see Content of Application, Budget, item 9; and Appendix I,
Budget Guidelines).
 
Preference will be given to units who meet the following
standards:
 
1.  The Principal Investigator should have previous
experience in participating in and/or managing multicenter
trials.
 
2. a.  The applying clinical unit should evaluate and treat
a minimum of 250 high-risk infants per annum, excluding:
infants with significant lung disease, i.e. requiring oxygen
at discharge; infants with congenital disorders of
respiratory or cardiac function; and infants of mothers who
currently abuse illicit drugs.
 
   b. The approximate number of high risk infants treated
      and evaluated per annum should be distributed among
      the following diagnostic categories: infants
      experiencing an ALTE,  SIDS siblings, symptomatic
      premature infants.  They should not be primarily
      premature infants.
 
o  Standards for the Clinical Trial Operations Center
 
1.  The unit must meet the above standards of the clinical
units and intend to participate in the study as a clinical
unit.
 
2.  The applicant should have experience in managing multi-
center pediatric studies regarding protocol support and data
collection.
 
3.  The applicant should have the resources and the
capability to serve as the primary communication link to the
Data Coordinating and Analysis Center.
 
o  Standards for Data Coordinating and Analysis Center
 
1.  The applicant must have demonstrated prior experience as
a coordinating and statistical center in multi-center
clinical studies.
 
 2.  The Principal Investigator, with other staff, must have
appropriate biostatistical, computational, data management,
and coordination expertise and capability.
 
3.  The applicant must have the ability to assist in
designing protocols and the data collection system.
 
4.  The applicant must have experience in developing and maintaining a
quality control system and monitoring quality assurance of data should
be demonstrated.
 
5.  The applicant must have experience in data monitoring, patient
tracking systems, and coordination.
 
6.  The Data Coordinating and Analysis Center will report
quarterly to the NICHD, and every six months to the Steering
Committee regarding accumulated data and clinical unit
performance.  The applicant should document the ability to
meet such reporting deadlines as well as the overall
timetable outlined under Research Scope.
 
7.  The applicant must be prepared to cooperate with the
clinical units and NICHD in all design, collection, and
analysis functions.
 
8.  The applicant must exhibit a preparedness to pursue
capitation of particular operational costs of the protocol
(see Content of Application, Budget, item 4; and Appendix I,
Budget Guidelines).
 
o  Direction and Management of the Study
 
1.  The Steering Committee.  The Steering Committee will be
responsible for the development of the study protocol, the
conduct of the study, and the preparation of publications.
The Committee will consist of clinical unit Principal
Investigators, the Principal Investigator of the Clinical
Trial Operations Center, the Principal Investigator of the
Data Coordinating and Analysis Center, the NICHD Program
Officer for Sudden Infant Death Syndrome Research, and the
Chief of the Biometry and Mathematical Statistics Branch of
NICHD.
The Clinical Unit which also serves as the Clinical
Trial Operations Center will have two representatives on the
Committee.
The NICHD Program Officer for Sudden Infant
Death Syndrome Research will serve as the Research
Coordinator for the study.
Each member of the Steering Committee will have one vote except
for the Chief of Biometry and Mathematical Statistics Branch who
will serve as a statistical consultant.
The
Steering Committee will also function as a publications
committee.
 
2.  Data Collection.  Data collection will be conducted in
three parts: (1) primary data collection, (2) primary
analysis of events on monitor records, and (3) central data
collection, and analyses of the aggregate database.
 
o  Primary data collection and quality assurance of medical
   and event records will be the responsibility of the
   individual clinical unit enrolling the patients.
 
o  Primary analysis of defined events on the monitor records
   will be performed according to a common protocol by a
   designated unit in a blinded fashion.
 
o  The Clinical Trial Operations Center will be housed at
   one of the clinical units and will serve as a resource
   for the other units.  It will support the sites in
   medical and clinical questions regarding protocol conduct
   and primary data collection to insure uniformity of
   protocol implementation.  It will serve as the primary
   central check point for the data prior to transfer to the
   Data Coordinating and Analysis Center.  It will collect
   the data from the clinical units, and ensure the
   completeness of the forms.
 
o  The Data Coordinating and Analysis Center will produce
   and maintain the computerized protocol database to
   include quality assurance of data, and will perform
   interim analyses of data.  Aggregate data analysis at the
   termination of the study will be directed by the Steering
   Committee, and will be conducted by the Data Coordinating
   and Analysis Center.
 
3.  The Data Safety and Monitoring Board.  A Data Safety and
Monitoring Board (DSMB) will monitor the safety of the
ongoing study and advise on its conduct.  It will be
selected by NICHD and will represent expertise in ethics,
clinical trial design, biostatistics, neonatology,
pediatrics, and pathology.  The DSMB is responsible to, and
will report to the Director of NICHD.
 
o  Research Scope.  The awardees are expected to cooperate
   with each other and with NICHD assistance for the design,
   initiation, and conduct of a multi-center clinical study
   of life-threatening events recorded in the home with
   state of the art apnea monitors and event recorders in
   high-risk infants.
 
The work accomplished under the Cooperative Agreements is
expected to follow this general outline (duration of phases
are estimates only):
 
Phase 1:  (12 months).  The Steering Committee will:
 
o  identify study objectives, considering the relevant
   research questions, and available resources.
 
o  develop the standard protocol and data forms.  The
   protocol should include criteria for the evaluation,
   enrollment, home monitoring, and follow-up of high-risk
   infants.  The outcome measures and data acquired should
   provide information on monitor compliance, the
   physiologic and clinical parameters of episodes of apnea
   and bradycardia, and how they may identify an infant at
   risk.
 
o  develop a standard system for analysis of event
   recordings and polysomnograms.
 
o  develop a database management system, with primary input
   from the Data Coordinating and Analysis Center, and
   consultant NICHD statistician.
 
o  adopt/develop standard manuals and training programs for
   physicians and parents to support the appropriate use of
   the monitors, and to optimize compliance.
 
o  adopt/develop standard autopsy, pathology, and death
   scene investigation protocols for all infant deaths
   within the first year of life.  It is also expected that
   procedures will be developed for acquisition and storage
   of tissue for future pathologic components of the study.
 
The Clinical Units, Clinical Trial Operations Center, and
Data Coordinating and Analysis Center will conduct a pilot
test of the protocol and data management system with a
limited number of infants.
 
The awardees will hire and train staff in preparation for
protocol implementation, and data management.
 
The Data Coordinating and Analysis Center will develop a
quality assurance system.
 
Note: Phases 2 and 3 will run concurrently.
 
Phase 2: (44 months).  The Clinical Units will evaluate, and
enroll patients into the protocol.  Every effort will be
made to recruit, and enroll minority populations.  The units
will collect data with adequate attention to the fidelity of
records and will provide information in uniform data format
for analysis.  The Data Coordinating and Analysis Center
will implement the data coordination and quality assurance
systems, and provide data summaries to the Steering
Committee as determined by the protocol.  Format and content
of final reports and the dissemination of information to the
scientific community will be determined by the Steering
Committee.
 
Phase 3: (30 months).  Based on reports of the aggregated
data, and recommendations of the Data Safety and Monitoring
Board, the Steering Committee will decide to modify the
protocol or determine the need to terminate the study
because the data is sufficient to meet the objectives of the
protocol.
 
o  CONTENT OF APPLICATION
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION
OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES
IN CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA
clinical research grants and cooperative agreements will be
required to include minorities and women in study
populations so that research findings can be of benefit to
all persons at risk of the disease or condition under study;
special emphasis should be placed on the need for inclusion
of minorities and women in studies of diseases, disorders,
or conditions which disproportionately affect them.  This
policy is intended to apply to males and females of all
ages.  If women or minorities are excluded or inadequately
represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale
should be provided.
 
The composition of the proposed study population must be
described in terms of gender and racial/ethnic group,
together with a rationale for its choice.  In addition,
gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for
the scientific objectives of the study.  This information
should be included in the form PHS 398 in Section 2, A-D of
the Research Plan AND summarized in Section 2, E, Human
Subjects.
 
Applicants/offerors are urged to assess carefully the
feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes
that it may not be feasible or appropriate in research
projects to include representation of the United States
racial/ ethnic minority populations (i.e., Native Americans
(including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics). The rationale
for studies on single minority population groups must be
provided.
 
Clinical Units:  The application should include the
following:
 
1.  The critical objectives of a research study of abnormal
cardiorespiratory events detected at home in infants on
apnea monitors, with the long term goal of improving the use
of apnea monitors to manage infants at risk.
 
2.  A sample protocol written specifically for this study to
serve as an indicator of the applicant's ability to
participate in the design and conduct of the protocol for
this cooperative investigation.
 
3.  Descriptions of the staff and programs in place for the
recruitment, evaluation, home monitoring, and follow-up of
infants at risk for a life-threatening event; proposals for
expansion of services if needed.
 
4.  Descriptions of pediatric subspecialty services, support
services and laboratories necessary for: evaluating infants,
monitoring infants on study, and investigating the cause of
death.
 
5.  Descriptions of available high risk patient populations.
Include a tabulation of high risk infants served in the last
three years providing gestational age at birth, sex,
race/ethnicity, birthweight, diagnosis, age at initiation of
monitoring, duration of monitoring, and outcome through the
first year of life (including loss to follow-up).  Provide
the system of patient referral, projections of patients
available in the next five years, and plans for expansion of
referral services if desired. The projections and plans for
expansion should describe the gender and race/ethnicity of
the population to be screened for study enrollment.
 
6.  Description of methods employed to determine compliance
with monitor use and results of compliance studies for the
last three years.
 
7.  Description of how the monitors are calibrated,
standardized, and quality controlled.  Provide a description
of how monitors and event recorders should be standardized
in the multi-center study, and a plan for quality assurance
to ensure that the data from captured events is uniform and
accurate from all centers.
 
8.  Protocol for scoring and analyzing events recorded from
home monitors to include cardiac, respiratory, and
oxygenation parameters.  Provide a sample data analysis
profile of how the data from the monitors should be
summarized to include the primary physiologic and clinical
variables.
 
9.  Description of clinical facilities and existing home
monitoring resources, including monitors, event recording
systems, and computers.
 
10.  Description of previous experience in clinical research
studies in scientific areas relevant to the proposed study,
including experience in managing multicenter clinical
studies.
 
11.  Statements from the department and the institutional
sponsored program office assuring cooperation with the
proposed plan to capitate particular operational costs for
the study (see Budget Guidelines, Appendix I).
 
12.  Investigators from institutions which have a General
Clinical Research Center (GCRC) funded by the NIH National
Center for Research Resources may wish to identify the GCRC
as a resource for conducting the proposed research.  In such
a case, a letter of agreement from the GCRC program director
or Principal Investigator could be included with the
application.
 
Clinical Trial Operations Center:  The application should
include all elements cited above for the Clinical Units, as
well as the separate section containing the following:
 
1.  Description of applicant's perception of their role in
the study.
 
2.  A plan detailing methods and function of personnel
involved in support of clinical units in: issues of protocol
implementation, data acquisition, and quality control.
 
3.  A description of administrative and data management
capability.
 
4.  Description of previous experience in managing multi-
center clinical research studies.
 
Data Coordinating and Analysis Center:
 
The application should include the following:
 
1.  Description of applicant's perception of their role in
the study.
 
2.  A plan detailing methods of data receipt, quality
control, analysis and reporting, including communication
with clinical and administrative personnel.
 
3.  A description of computing and data processing
capability.
 
4.  Description of previous experience in managing multi-
center clinical research studies.
 
5.  Statements from the department and the institutional
sponsored program office assuring cooperation with the
proposed plan to capitate particular operational costs for
the study (see Budget Guidelines, Appendix I).
 
MECHANISM OF SUPPORT - Terms of the Agreement
 
The funding mechanism to be used to assist the scientific
community in undertaking this system of clinical
investigation will be Cooperative Agreements between the
participating units and NICHD.  The major difference between
a Cooperative Agreement and a research grant is that there
will be substantial programmatic involvement of NICHD staff
above and beyond the levels required for traditional program
management of grants.  All parties will agree to accept the
coordinating role of the group and the participatory and
cooperative nature of the group process.
 
Specifically the role of the NICHD Research Coordinator will
be to aid the awardees and the Steering Committee in the
following ways:
 
o  Assistance in the identification of the objectives of the
   study.
 
o  Assistance in the development of the study protocol and
   data management procedures.
 
o  Assistance in the review and evaluation of each stage of
   the program before subsequent stages are started, and in
   interim and final analysis, in conjunction with the
   Principal Investigators and the Steering Committee.
 
o  Assistance in reporting results to the community of
   investigators and health care recipients.
 
Programmatic responsibility for review and oversight of the
Cooperative Agreements will reside with the NICHD Research
Coordinator.  This role will include the following:
 
o  Assurance of the scientific merit of the study, including
   the option to withhold support of a participating center
   if technical performance requirements such as protocol
   compliance, enrollment targets, completeness and
   integrity of database, are not met.  Alternatively,
   determine the need to add units, and to invite
   applications through publication of an RFA for additional
   cooperative agreements.
 
o  Assistance on the efficient conduct of the study,
   including ongoing review of progress; redirection of
   activities to improve performance and cooperation if
   necessary; and frequent communication with other members
   of the Steering Committee.
 
o  Initiation of a decision to modify or terminate a study
   based on the advice of the Data Coordinating and Analysis
   Center, Data Safety and Monitoring Committee, and the
   mutual consent of the Steering Committee.

The responsibilities and authorities of the awardees will be
as follows:
 
o  Identification of objectives and approaches of the study.
 
o  Development and implementation of the protocol.
 
o  Collection and transmission of accurate data in a timely
   manner.
 
o  Analysis of data and publication of results.
 
The support of awards pursuant to this RFA is contingent
upon the receipt of appropriated funds for this
purpose.  The number of Clinical Unit awards will be
influenced by the overall merit of the applying units, and
by the amount of funds available to the Institute.  One Data
Coordinating and Analysis Center Award will be made.  Up to
$ 1,500,000 in direct costs has been set aside for the first
year of these Cooperative Agreements, and it is anticipated
that five meritorious applications, including the Data
Coordinating and Analysis Center, will be funded.  The
planned project period is five years, and it is anticipated
that the study will be completed in this time period.  A
decision will be made at the appropriate time to re-release
the RFA for re-competition if it appears that the study
cannot be completed in the initial award period.
 
Arbitration procedures will be instituted in addition to the
customary programmatic and financial negotiations which
occur in the administration of grants, only when agreement
cannot be reached on scientific programmatic issues
between the awardee and the NICHD Research Coordinator
that may
arise after the award.
In that event, an arbitration panel
will be formed consisting of one person selected by the
Principal Investigator, one person selected by the Research
Coordinator, and a third person selected by these two
members.  The decision of the arbitration panel will be
binding.  These special arbitration procedures in no way
affect the right of a recipient of a cooperative agreement
to appeal an adverse determination under the terms of PHS
regulations at 42 CFR Part 50, Subpart D, and DHHS
regulations at 45 CFR Part 16.
 
The specific program-related terms and conditions of the
Cooperative Agreement, including those relating to
arbitration procedures, will be included in the Notice of
Grant Award.  The terms of Award of Cooperative Agreement
are in addition to, and not in lieu of, otherwise applicable
OMB administrative guidelines, DHHS grant administration
regulations at 45 CFR Part 74, and other DHHS, PHS, and NIH
grant administration policies.    Business management
aspects of these awards will be administered by the NICHD
Grants Management Branch in accordance with DHHS, PHS, and
NIH grant administration requirements.
 
REVIEW CRITERIA AND PROCEDURES
 
o  Review Procedures
 
Applications that are nonresponsive
to this RFA will be screened out by NICHD staff upon receipt
and returned to the applicants without further
consideration.  Applications will be considered non-
responsive if they do not meet the minimum standards listed
above.  If the required information concerning inclusion of
women and minorities in clinical research study populations
is not contained within the application, the application
will be returned.  Applications which are complete and
responsive may be subjected to a preliminary evaluation by a
NICHD peer review group to determine their scientific merit
relative to the other applications received in response to
this RFA (triage); the NICHD will withdraw from further
consideration applications judged to be noncompetitive for
award and promptly notify the Principal Investigator/Program
Director and the official signing for the applicant
organization.  Those applications judged to be competitive
will be further evaluated for scientific/technical merit by
a special review committee convened specifically for this
purpose by the Division of Scientific Review, NICHD.  This
will be followed by a second-level review by the National
Advisory Child Health and Human Development Council.  Final
selection of clinical centers for funding may also be based
on the need for diversity in the study population.
 
o  Criteria for Review of Clinical Units
 
Applications meeting the minimum standards will be evaluated
on technical merit according to the criteria listed below.
 
1.  Qualifications, experience, and commitment of key
personnel; scientific, clinical, and administrative
abilities of the Principal Investigator and other team
members; knowledge and experience in areas relevant to the
conduct of the proposed study pertaining to the clinical,
laboratory, and postmortem evaluation of infants at risk for
a sudden death or an apparent life-threatening event;
commitment of staff time for the satisfactory conduct of the
study; experience and qualifications of team members who
would be responsible for internal activities of data
analysis and management.
 
2.  Protocols and Procedures.  Willingness to work and
cooperate with other awardees and the NICHD in the manner
summarized in this RFA; quality of the sample protocol
proposed, including scientific objectives, design, and
ethical and human subject matters.
 
Peer reviewers will address specifically whether the
research plan in the application conforms to the policy
concerning inclusion of women and minorities in clinical
research.  If the representation of women or minorities in
the sample study design is inadequate to answer the
scientific question(s) addressed AND justification for the
selected study population is inadequate, it will be
considered a scientific weakness or deficiency in the study
design and will be reflected in assigning the priority score
to the application.
 
3.  Resources, Facilities, and Management.  Adequacy of
professional and patient resources, and administrative,
clinical, and data management facilities as described in the
minimum requirements; institutional assurance to provide
support to the study in such areas as fiscal administration,
personnel management, space allocation, procurement,
planning, and budgeting.
 
4.  Budget.  Appropriateness of proposed budget in light of
budget guidelines outlined in Appendix I.  Adequacy of
documentation of willingness to follow capitation of
specific operational costs.
 
o  Criteria for review for the Clinical Trial Operations
   Center Applicants will be evaluated separately on their
   merit as Clinical Trial Operations Center from their
   merit as Clinical Units.  They will receive a separate
   priority score for each function. Applications meeting
   the minimum standards will be evaluated on technical
   merit according to the following:
 
1.  Qualifications, Experience, and Commitment of Key
Personnel.  Scientific, clinical, and administrative abilities
of the Principal Investigator and other team members in
coordinating multicenter clinical studies.
 
2.  Protocols and Procedures.  Willingness to work and
cooperate with other awardees and the NICHD in the manner
summarized in this RFA; quality of the sample plan to
support protocol implementation, and data receipt and
coordination.
 
3.  Resources, Facilities, and Management.  Adequacy of
professional resources and administrative, clinical, and
data management facilities as described in the minimum
requirements.
 
4.  Budget.  Appropriateness of proposed budget in light of
Clinical Trial Operating Center budget guidelines outlined
in Appendix I.  Adequacy of documentation of willingness to
follow capitation of specific operational costs.
 
o  Criteria for review for the Data Coordinating and
   Analysis Center
 
Applications meeting the minimum requirements will be
evaluated on technical merit according to the criteria
listed below.
 
1.  Qualifications, Experience, and Commitment of Key
Personnel.  Scientific and administrative abilities of the
Principal Investigator and other team members; experience of
the Principal Investigator and other key personnel in
statistical, data management, quality control, study
coordination, and administrative aspects of multicenter
clinical studies; commitment of staff time for satisfactory
conduct of the study; understanding of the scientific
objectives and outline of the proposed multicenter
cooperative investigation as evidence by discussion of
design, recruitment, and implementation issues.
 
2.  Protocols and Procedures.  Quality of proposed plan for
study coordination, data collection and monitoring;
discussion of ability to meet proposed timetable;
willingness to work cooperatively with the clinical units
and NICHD in the manner summarized in this RFA.
 
3.  Facilities and Management.  Evidence of satisfactory
facilities and supporting environment, including space and
equipment for work proposed (any new equipment requested
under this award must be adequately justified); evidence of
institutional support for participation in a long term
collaborative program.
 
4.  Budget.  Appropriateness of proposed budget in light of
budget guidelines outlined in Appendix I.  Adequacy of
documentation of willingness to follow capitation of
specific operational costs.
 
METHOD OF APPLYING
 
o  Application Procedure
 
Applications should be submitted on form PHS 398 (revised
10/88) which includes appropriate documentation regarding
the protection of human subjects.  The conventional
presentation format for regular research grant applications
should be used, with care taken to address the points
identified under review criteria and eligibility for
participation.
 
The RFA label (found in the 10/88 revision of application form PHS 398)
must be affixed to the bottom of the face page of the original copy of
the application.  Failure to use this label could result in delayed
processing of your application such that it will not reach the review
committee in time for review.
 
The phrase "APNEA COOPERATIVE AGREEMENT APPLICATIONS, RFA
HD-91-02" must be typed in item 2 of the face page of the
application.  The original and four copies of the
application must be sent or delivered to:
 
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
Also send two copies to:
 
Laurance S. Johnston, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
Executive Plaza North, Room 520
Bethesda, MD  20892
 
o  Application Deadline
 
Applications including copies must be received by June 10,
1991.  Late applications will not be accepted.
 
o  Timetable
 
Application Receipt Date: June 10, 1991
Initial Review Date: July 1991
Review by Advisory Council:  September 1991
Anticipated Award Date:  September 30, 1991
 
o  Additional Information:  Inquiries regarding scientific
   or programmatic issues may be directed to:
 
Marian Willinger, Ph.D.
Health Scientist Administrator
Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
Executive Plaza North, Room 643
Bethesda, MD  20892
Telephone:  (301) 496-5575
 
Inquiries regarding grants management and administrative
policy may directed to:
 
Douglas Shawver
Supervisory Grants Management Specialist
Grants Management Branch
Office of Grants and Contracts
National Institute of Child Health and Human Development
Executive Plaza North, Room 505
Bethesda, MD  20892
Telephone:  (301) 496-1303
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.865, Research for Mothers and Children.
Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC241), and administered under
PHS grant policies and Federal Regulations 42 CFR Part 52
and 45 CFR Part 74.  This program is not subject to review
under the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.
 
APPENDIX I
 
BUDGET
 
Clinical Units:
The budget at the time of application will consist of (1) a
base budget, and (2) capitated services as outlined below.
 
1.  Base budget
    Principal Investigator/ Co-Principal       30% effort
    Study Coordinator                      100% effort
    Administrative Assistant                    20% effort
    Supplies and small equipment               $ 5,000
    Travel: For year one, four trips to Bethesda for the
 
Principal/Co-Investigator team, and two trips for the
research team.  For years two through five, three trips to
Bethesda for the Principal/Co-Investigator team, and one
trip for the research team.
 
2.  Capitated services:  These are services above standard
clinical care for infants enrolled in a monitoring program.
The cost per patient, and total cost based on estimated
annual enrollment rates, should be included.  Keep in mind
that enrollment in the first year will be restricted to
pilot studies.
 
Research nurse: nursing staff required to perform clinical
and monitoring support functions stipulated as research in
the sample protocol.
 
Monitor/recording systems: Only items above the standard of
care home monitoring equipment, such as event recorders, and
monitors of oxygen saturation, should be included.
 
Polysomnograms:  It is anticipated that approximately two
polysomnograms beyond the standard entry evaluation will be
conducted at specified intervals during the course of the
study.
 
Pathology Services: Estimate costs for infants dying within
the first year of life based on previous three years of
monitoring experience.
 
At such time as an application has been approved  and is
being considered for funding, the applicant will be required
to complete the budgets based on capitation funding.  Each
clinical unit will be given base costs (listed above) in
addition to a flat fee per patient.  When protocol
development is near completion, a final per patient fee will
be determined, which will   include costs which cannot be
estimated at this time, such as scoring and analysis of
event recordings.
 
After protocol initiation, the individual members will be
required to project patient enrollment during a specified
time frame and an award will be made based on this
projection; continuation and level of funding for future
years will be based on the number of patients successfully
enrolled and completed.  The clinical units approved to
serve as the Clinical Trial Coordinating Center, and to
perform event recording analysis will be awarded additional
funds to perform these functions.
 
Clinical Trial Operations Center:
 
The budget at the time of application will consist of a base
budget with maximum allowances.  Estimates for capitated
costs cannot be made without a protocol and knowledge of the
size of the extent of patient and data management. The
maximum allowances are outlined below.
 
1.  Base Budget
    Principal Investigator                      15% effort
    Study Coordinator/Research Nurse          50% effort
 
Data Coordinating and Analysis Center:
The budget at the time of application will consist of a base
budget.  Estimates for capitated costs cannot be made
without a protocol and knowledge of the size of the data
base. The maximum allowances are outlined below.
 
1.  Base Budget
    Principal Investigator/Biostatistician team     50% effort
    Programmer/ System Analyst                    50% effort
    Study Coordinator/Administrative Assistant  50% effort
    Supplies and small equipment                 $  8,000
    Travel: For year one, four trips to Bethesda for the
Principal/Co-Investigator team, and two trips for the
research team.  For years two through five, three trips to
Bethesda for the Principal/Co-Investigator team, and one
trip for the research team.
 
2.  Examples of capitated services which will be awarded in
the future include:
 
Data entry operator
Publication costs: printing and duplication of forms
Distribution and storage of forms
Service contracts
 
At such time as an application has been approved and is
being considered for funding, the applicant will be required
to complete the budgets based on capitation funding.  The
Data Coordinating and Analysis Center will be given base
costs (listed above) in addition to a flat fee per patient.
When protocol development is near completion, a final per
patient fee will be determined.
 
After protocol initiation, an award will be made for
capitated costs based on the total projected enrollment for
a specific time frame; continuation and level of funding for
future years will be based on the number of patients
successfully enrolled and completed in the study.