Subject: RFA AI-9l-05 2/l/9l NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 06 Feb 91 07:28 EST

Good Morning Paul,
    There were several errors in the 2/l/9l NIH Guide and RFAs that
came down the wire.  I am sending over revised versions this morning
that came from NIH yesterday.
    Can you exchange these with the version of the ones that were
posted last week?  It would be most appreciated.  Please notify when
done so I can alert the others of the changes.
    Please post this one as: RFAAI-91-05.910201
Thanks.    Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS
 
DEVELOPMENT OF MODELS FOR PLACENTAL
AND PEDIATRIC METABOLISM, TOXICITY, AND TRANSPORT OF anti-HIV
DRUGS
 
RFA:  AI-91-05
 
P.T. 34; K.W. 0785170, 0715008, 0740012, 1007009, 0755025
 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  March 11, 1991
Application Receipt Date:  April 22, 1991
 
The National Institute of Allergy and Infectious Diseases
(NIAID) invites applications for individual research project
(RO1) grants to conduct basic research in the development of
animal models and in vitro models to assess the metabolism,
transport, and toxicity of anti-HIV drugs in the placenta, the
fetus and the neonate.  HIV is now recognized as the causative
agent of the Acquired Immunodeficiency Syndrome (AIDS).  Children
born to HIV-positive mothers and HIV-infected women are now the
fastest growing populations of AIDS patients.  Traditionally,
new therapies were available to children and pregnant women only
after extensive clinical experience in other adult populations.
However, because of the magnitude and severity of the AIDS
epidemic, therapies are now being tested in children and
pregnant women early in clinical development.  Frequently, there
is minimal information available from preclinical studies to
provide a scientific basis for the use of therapeutics in these
specific patient populations.
 
Some of the therapeutic agents now in use or being considered
for use in clinical trials of pregnant women and their children
include:  azidothymidine (AZT), dideoxyinosine (ddI), other
nucleoside analogs, soluble CD4-conjugates, protease inhibitors,
and immunoglobulins.  Animal models and in vitro models are
needed to assess the metabolism and transport of AIDS therapies
in the placenta and in the fetus and neonate.  In addition, the
mechanisms of toxicity of therapeutics to the placenta, fetus,
and neonate must be examined.  This preclinical information will
facilitate optimizing the efficacy and minimizing the toxicity
of drugs evaluated in these patient populations.
 
NIAID now wishes to stimulate research to develop animal models
and in vitro models to assess the metabolism, transport, and
toxicity of anti-HIV drugs in the placenta, fetus, and
neonate.  Applications that involve collaborating scientists or
institutions are encouraged but not required for response to
this announcement.  Research plans to evaluate standard
teratology, reproductive toxicology, or pharmacokinetics in
rodents are not considered responsive to this announcement.
 
I.    BACKGROUND
 
NIAID is playing a central role in the investigation of
AIDS.  Research efforts directed
toward the pathogenesis, prevention, and treatment of the disease
and its sequelae have intensified.  The NIAID has undertaken a
lead role in organizing scientists into National Cooperative
Drug Discovery Groups for the Treatment of HIV infection (NCDDG-
HIV) and of the opportunistic infections associated with AIDS
(NCDDG-OI).  In vitro screening of potential therapies and the
more targeted approach of the NCDDG's have proven extremely
valuable and have led to identification of several new therapies
currently undergoing preclinical development as well as several
therapies in clinical trials.  The NIAID also supports
individual investigators in their research efforts toward the
discovery and development of therapies for AIDS.  The NIAID
oversees and supports the AIDS Clinical Trials Groups who
conduct clinical trials to evaluate therapies for HIV
infections and the opportunistic infections associated with
AIDS.
 
To date, most preclinical drug development efforts have
concentrated on generating data in support of clinical trials in
HIV-infected adults.  Preclinical studies to investigate the
unique aspects of treating pregnant women who are HIV-positive
or their children need to be expanded.  Treatment of infants is
complicated by the fact that approximately 30% of children born
to HIV-positive mothers are infected with HIV, while about 70%
are uninfected.  Currently, there are no methods readily
available to determine before or soon after birth which children
are actually infected.  Thus, consequences of exposure to
therapies in uninfected children must be considered.  The NIAID
wishes to expand the scope of research currently being conducted
to examine pharmacology, pharmacokinetics, and toxicity issues
that are specific to optimizing the use of AIDS therapies in
pregnant women and children.
 
The optimal design of clinical trials of AIDS therapies in HIV-
positive pregnant women and their infants requires a basic
understanding of the pharmacology, pharmacokinetics, and
mechanisms of toxicity of AIDS therapeutic agents in these
populations.  There is a paucity of information related to
mechanisms of drug handling and toxicity of therapeutics used to
treat HIV-infected pregnant women and their children.
Aggressive research is necessary to develop models in which
questions of mechanism of transplacental transfer, placental and
fetal metabolism, and placental and developmental toxicity of
AIDS therapies may be answered.  Specifically, models are needed
to:  (i) define mechanisms of transport of therapies across the
placenta; (ii) investigate metabolism of therapies in the
placenta, fetus, and neonate; (iii) define the
distribution and pharmacokinetics parameters of drugs
administered to pregnant and neonatal animals; (iv) elucidate
the mechanisms of toxicity related to AIDS therapies in the
placenta, fetus, and neonate.
 
II.  OBJECTIVES AND SCOPE
 
NIAID wishes to stimulate research to develop animal models and
in vitro models to assess the metabolism, transport, and
toxicity of anti-HIV drugs in the placenta and in the fetus and
neonate.
 
Specifically, research efforts considered responsive to this RFA
are to develop and use:  (i) in vitro models to assess the
metabolism, transport, and mechanisms of toxicity of anti-AIDS
therapies in the placenta; (ii) animal models to assess the
transplacental transport of AIDS therapies and to determine
pharmacokinetics parameters to serve as the basis for clinical
trials in humans; (iii) animal models to assess the metabolism
and distribution of AIDS therapies in the fetus and neonatal
animals to serve as the basis for clinical trials in humans;
(iv) animal models to assess mechanisms of toxicity relevant to
use of drugs in pregnant women and very young infants.  The
emphasis should be on issues of pharmacology and toxicity that
are specific to the use of AIDS therapies in pregnant women and
children born to HIV-positive women.  The Developmental
Therapeutics Branch of the Division of AIDS will assist in
providing therapeutic agents to be studied and, where possible,
analytical methods for detection of drug.
 
It has been presumed that in order for a therapy to be most
effective in preventing prenatal/perinatal transmission of HIV,
the therapy must cross the placenta.  Because the exact timing of
infection of the fetus with HIV is not known, drugs have been
sought that exert anti-viral activity in maternal tissues and in
the fetus; this requires transport of the therapeutic from
maternal to fetal circulation.  However, little is known about
the mechanisms of transplacental transport for most AIDS
therapies now in the clinic or proposed for use in pregnant
women.  Therefore, models are needed to define the transport of
drugs either in vitro, using human placentae, or in animals such
as non-human primates having placental structure and function
similar to humans.  The information gained from these models
should be applicable to the design of clinical trials in
pregnant women.
 
Similar models to those developed for the transport studies
described above are needed to define the pharmacokinetics
parameters for therapies to be used in HIV-positive pregnant
women and neonates.  For example, information on drug clearance
in pregnant versus non-pregnant animals, on the plasma half-time
of drugs in maternal and fetal circulation, on accumulation of
drug in the amniotic fluid, and pharmacokinetics in the neonate
would contribute greatly to the preclinical development of new
therapies and the design of clinical protocols.
 
The capacity to metabolize drugs varies with tissue and organ
type and with age.  The placenta itself contains a variety of
enzymes, including p450s that metabolize drugs.  The human fetus
has very limited capacity to metabolize drugs, but metabolic
enzymes increase during late gestation and in the early
postnatal period.  These metabolic parameters may affect the
distribution and pharmacokinetics of administered drugs.  Thus,
there is a need to investigate, using human placenta in vitro
and animal models, the metabolism of AIDS therapies within the
placenta, in the fetus, and in the neonate.  The information
from these studies should assist in the interpretation of data
on transport and pharmacokinetics of therapeutic agents.
 
Treatment of HIV-infected pregnant women and their potentially
uninfected infants in utero requires that the consequences of
exposure to therapy be considered.  Toxicity related to
treatment may occur directly, affecting the function of the
placenta.  For example, drugs that demonstrate placental
toxicity may act on the microvasculature of the placenta.  Other
mechanisms of direct toxicity are related to regulation of
hormones necessary to maintain placental function.  Questions of
direct placental toxicity may be examined using human placenta
in vitro or using animal models with placental function similar
to humans.
 
Drugs may also have toxic effects on the fetus exposed to drug
in utero, or on the neonate directly receiving drug.  These
effects may range from frank terata to subtle effects on
developmental progress observed only much later.  In addition,
toxic effects, as defined in adult animals or humans, may differ
in organisms still undergoing development.  For example,
neurotoxicity that may be clearly defined in adults may appear
as a more diffuse, generalized syndrome if exposure occurred
during development.  While standard protocols exist and are
routinely used for assessing the teratogenic potential of drugs,
the more delayed effects are not well studied or understood.
Thus, models in which to investigate the effects of therapy on
the developing organism are needed; special attention needs to
be paid to effects on development of the immune system and
immune function and on the nervous system, examining development
of motor, sensory, and cognitive function.  Information from
these model systems would be invaluable in the design of
clinical trials using therapies during pregnancy and during
early infancy.
 
Research plans to evaluate standard teratology, reproductive
toxicology, or pharmacokinetics in rodents are not considered
responsive to this announcement.
 
III.  MECHANISM OF SUPPORT
 
This Request for Applications (RFA) will use the R01 grant mechanism.  The
NIAID has
allocated $1,000,000 (total costs) for the initial year of
funding applications received in response to this RFA.  It is
anticipated that three to five applications will be funded.  The
award of grants pursuant to this RFA is contingent upon the
continuing availability of funds for this purpose and upon
receipt of a sufficient number of applications of high
scientific merit.
 
This RFA is a one-time solicitation.  Generally, future
unsolicited competing continuation applications will compete
with all investigator-initiated applications and be reviewed by
a DRG study section.  However, should the NIAID determine that
there is a sufficient continuing program need, the NIAID may
announce a request for renewal applications.
 
IV.  MINIMUM REQUIREMENTS FOR APPLICATION
 
Any domestic or foreign institution, university, medical
college, hospital, and laboratory or other public, private or
for-profit institution is eligible.  Applicants may request up
to four years of support.
 
V.  LETTER OF INTENT
 
Prospective applicants are asked to submit, by March 11, 1991, a
letter of intent that includes a descriptive title and a
description (not to exceed one page) of the proposed research.
The letter of intent is requested in order to provide an
indication of the number and scope of applications to be
reviewed.
The letter of intent does not commit
the sender to submit an application, nor is it a requirement for
submission of an application.  The letter of intent should be
sent to:
 
      Polly R. Sager, Ph.D.
      Senior Scientist
      Developmental Therapeutics Branch
      Division of AIDS, NIAID
      6003 Executive Blvd., Room 244P
      Bethesda, MD  20892
      FAX number:  (301) 480-5703
 
VI.  CONSEQUENCES OF LACK OF RESPONSIVENESS TO THE RFA
 
Applications that are incomplete for review or nonresponsive to
this RFA will be screened out by NIH staff upon receipt and
returned to the applicants without further consideration.
 
VII.  REVIEW METHOD AND PEER REVIEW CRITERIA
 
Those applications that are complete and responsive may be
subjected to a triage by a peer review group to determine their
scientific merit relative to the other applications received in
response to this RFA.  The NIH will withdraw from competition
those applications judged by triage to be noncompetitive and
notify the applicant and institutional business official.
 
Those applications judged to be competitive will be further
reviewed for scientific and technical merit by a Review
Committee convened by the Division of Research Grants, NIH.  The
second level of review will be provided by the National Advisory
Allergy and Infectious Disease Council.
 
Awards will be based on scientific and technical merit
significance, originality, adequacy of research experience,
commitment, and time availability of the Principal Investigator
and other key personnel, adequacy of facilities, and reasonableness of
cost.
 
VIII.  METHOD OF APPLYING
 
A.  Receipt Date
 
The deadline for receipt of applications is April 22, 1991.
Applications received after this date will be considered as not
responsive to this RFA and will be returned without review.
 
B.  General
 
1.  The research grant application form PHS-398 (rev.
10/88) must be used in applying.  These forms are available at
most institutional business offices and from the Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 499, 9000 Rockville
Pike, Bethesda, Maryland 20892.
 
Submit a signed, typewritten original of the application,
including the Checklist, and 23 signed, exact, single-sided
photocopies, in one package to:
 
      Division of Research Grants
      National Institutes of Health
      Westwood Building, Room 240
      Bethesda, MD  20892**
 
2.  TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH THIS
RFA:
 
      a.  The application form must have "DEVELOPMENT OF
      MODELS FOR PLACENTAL AND PEDIATRIC METABOLISM, TOXICITY,
      AND TRANSPORT OF anti-HIV DRUGS" (RFA AI-91-05) typed on
      line 2 of the face page of the application form.
 
      b.  The RFA label provided with the instructions must be
      affixed to the bottom of the face page.  Failure to use
      this label could result in delayed processing of your
      application so that it may not reach the review committee
      in time for review.
 
IX.  INQUIRIES
 
Additional information may be obtained from:
 
      Polly R. Sager, Ph.D.
      Developmental Therapeutics Branch
      Division of AIDS, NIAID
      6003 Executive Blvd., Room 244P
      Bethesda, MD  20892
      Telephone:  (301) 496-0636
 
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and Transplantation
Research.  Grants are awarded under the authority of the Public
Health Service Act, Title IV, Section 301, as amended, Public
Law 78-410, Public Law 97-219, Public Law 99-158, Public Law 99-
500, and Report 99-711 to accompany HR 5233 and administered
under PHS grant policies and Federal Regulations 42 CFR 52 and
45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.