FYI LOI due Oct. 27 and full Nov. 27 (http://grants.nih.gov/grants/guide/rfa-files/RFAAI-06-035.html).
Through this RFA, the NIAID invites research grant applications that will support the
discovery, design, and/or development of novel therapeutics and/or post-exposure
prophylactics and rapid and sensitive diagnostics for certain biodefense toxins: Shiga
toxins, ricin toxin, the Staphylococcus enterotoxin B (SEB), Clostridium perfringens
epsilon toxin and the botulinum neurotoxins
(http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm).
Translational research to support, or which might lead to, the development of
therapeutics or diagnostics for biodefense toxins, as well as advanced product
development, are encouraged. Projects may include, but are not limited to, target
identification (e.g., compound screenings, epitope identification); the adaptation of
platform technologies or products to biodefense applications; development of high
throughput screening assays; novel approaches to delivering drugs to specific cell types;
approaches that link drug delivery to drug discovery; discovery and evaluation of
candidate inhibitors; selection, evaluation, and characterization of lead inhibitors;
optimization of products; process development, early validation and testing; preclinical
evaluation; scale-up, and production of quantities sufficient for preclinical regulatory
requirements and clinical Phase I testing or field trials.
Applications that include collaborations between researchers from different disciplines
and/or with industry (e.g., pharmaceutical, chemical or biotechnological companies) are
strongly encouraged. This RFA will not support basic research.
1. Research Objectives
Purpose
Research supported and conducted by the National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health (NIH), strives to diagnose, understand,
treat and ultimately prevent the myriad infectious, immunological, and allergic diseases
that impact millions of human lives. The NIAID Division of Microbiology and Infectious
Diseases (DMID) and the Division of Allergy, Immunology and Transplantation (DAIT)
support extramural research to control and prevent diseases caused by virtually all
infectious agents. This includes basic biomedical research, such as studies of microbial
physiology and antigenic structure; immunity; applied research, including the
development of diagnostic tests; and clinical trials to evaluate experimental drugs and
vaccines.
Through this RFA, the NIAID invites research grant applications that will support the
discovery, design, and/or development of novel therapeutics and/or post-exposure
prophylactics and rapid and sensitive diagnostics for certain biodefense toxins: Shiga
toxins, ricin toxin, the Staphylococcus enterotoxin B (SEB), Clostridium perfringens
epsilon toxin and the botulinum neurotoxins
(http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm). Translational research to
support, or which might lead to, the development of therapeutics or diagnostics for
biodefense toxins, as well as advanced product development, are encouraged. Projects
may include, but are not limited to, target identification (e.g., compound screenings,
epitope identification); the adaptation of platform technologies or products to biodefense
applications; development of high throughput screening assays; novel approaches to
delivering drugs to specific cell types; approaches that link drug delivery to drug
discovery; discovery and evaluation of candidate inhibitors; selection, evaluation, and
characterization of lead inhibitors; optimization of products; process development, early
validation and testing; preclinical evaluation; scale-up, and production of quantities
sufficient for preclinical regulatory requirements and clinical Phase I testing or field
trials. Applications that include collaborations between researchers from different
disciplines and/or with industry (e.g., pharmaceutical, chemical or biotechnological
companies) are strongly encouraged. This RFA will not support basic research.
For some biodefense toxins, models for the testing of candidate therapeutics may be
lacking, therefore, the development of new or improved animal models, as well as
alternatives to animal models, will be responsive. However, the investigator must present
strong evidence that an adequate model is lacking and that this will inhibit the testing of
candidate therapeutics. The investigator must also present compelling justification that
the proposed new or improved model is needed to facilitate the testing of candidate
therapeutics, and is feasible and appropriate.
NOTE: While clinical development strategies may be included within an overall product
development plan, this RFA will NOT support clinical trials, as defined in
http://www.niaid.nih.gov/ncn/glossary/default2.htm#clintrial. Applications requesting
support for clinical trials will be viewed as unresponsive to this RFA and will be returned
to the applicant without review. Collection and utilization of human derived material
required for therapeutic or diagnostic development, or for compliance with regulatory
requirements is considered responsive. Collection of all specimens must comply with the
requirements and policies of the NIAID, DMID
(http://www.niaid.nih.gov/dmid/clinresearch/) and 45 CFR Part 46.
NOTE: Applications proposing the development of a therapeutic or diagnostic that does
not focus on one or more of the biodefense toxins specified above (Shiga toxins, ricin
toxin, the Staphylococcus enterotoxin B (SEB), Clostridium perfringens epsilon toxin and
the botulinum neurotoxins) will be deemed unresponsive and will be returned to the
applicant without review.
NOTE: Applications addressing therapeutics or diagnostics for the NIAID Category B
bacteria that produce Shiga toxins (diarrheagenic E. coli and Shigella) are not responsive
to this RFA, and should be directed to the companion solicitation (RFA AI-06-029,
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-06-029.html)
NOTE: This RFA will NOT support research on environmental or workplace detection
technologies or targets. Diagnostics applications must focus on the goal of detection and
identification of toxins in human clinical samples.
Partnerships
A key component of this initiative is the development of partnerships between
researchers from different disciplines and/or with industry. Cooperative research that
brings together expertise in different aspects of research and product development is
strongly encouraged.
For the purpose of this RFA, industry is defined as large and small, domestic or foreign,
pharmaceutical, biotechnology, bioengineering, and chemical companies. Since academic
organizations are often the source of new candidate products, this RFA will also support
a partnership between industry and collaborator(s) as necessary from academic and non-
profit research organizations. Such partnerships are strongly encouraged, but not
required.
The Principal Investigator of the project may be affiliated with any of the eligible
institutions listed in Section III below. It is expected that in the application the Principal
Investigator will describe in detail the relevant product development expertise and track
record available within the team.
The NIH project scientist assigned to the project post-award will ensure that issues are
addressed and milestones met during product development. It is recognized that early
research and development steps may not be successful, and may need to be modified or
reworked. NIAID staff, through the cooperative agreement grant mechanism, will be
actively involved in evaluating progress toward project milestones and determining
whether continued investment is warranted. To receive consideration for funding of each
successive year, the annual progress report and an updated product development plan
must be received 2 months prior to the end of the current funding period, demonstrating
that the milestones defined for that funding year have been met.
Background
The NIH and other agencies in the Department of Health and Human Services (DHHS)
are currently supporting extramural and intramural projects to develop new products to
protect the public from the health consequences resulting from the use of biological
agents in acts of terrorism or war. The biological agents deemed to pose the greatest
threat to civilian populations are prioritized in the NIAID Category A, B and C priority
pathogens and toxins list, which is available at:
http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm. The NIAID convened three
Blue Ribbon Panels to address the research priorities for Category A pathogens and
toxins, Category B and C pathogens and toxins, and immunology research. The research
agendas that resulted from these three meetings are published at:
http://www.niaid.nih.gov/biodefense/research/biotresearchagenda.pdf,
http://www.niaid.nih.gov/biodefense/research/categorybandc.pdf and
http://www.niaid.nih.gov/publications/pdf/biodimmunpan.pdf.
In addition to the NIAID research agendas, the DHHS has identified the highest priority
products for bioterror preparedness
(http://www.niaid.nih.gov/biodefense/research/high_priority.htm).
Several expert panel meetings were also convened to address research needs for
developing therapeutics or diagnostics for the botulinum neurotoxins, ricin, and Shiga
toxins (http://www3.niaid.nih.gov/Biodefense/PDF/bot_toxins.pdf;
http://www3.niaid.nih.gov/Biodefense/PDF/bot+toxins+mtg.pdf;
http://www3.niaid.nih.gov/Biodefense/PDF/Report+BoNT.pdf;
http://www3.niaid.nih.gov/Biodefense/ricin_meeting.pdf;
http://www.niaid.nih.gov/dmid/enteric/hus_prevent.htm).
To meet the objectives outlined by the Blue Ribbon Panels, it is imperative that
promising findings are translated rapidly into product development. The involvement of
diverse disciplines within academia and industry in basic science, translational research
and product development is needed to bring sufficient expertise to bear on the
development of well-designed therapeutics and medical diagnostics.
Research Goals and Objectives
The objective of this RFA is to support scientifically sound, original and innovative
research that will advance the development of a therapeutic or diagnostic that is specific
for one or more of the following toxins: Shiga toxins, ricin toxin, the Staphylococcus
enterotoxin B (SEB), Clostridium perfringens epsilon toxin or the botulinum neurotoxins.
Projects are not required to result in a final product since clinical trials are not supported;
however proposals to make significant progress along the pre-clinical research and
product development pathway are expected. Therapeutics development may extend to
the point where the R34 Clinical Trial Planning Grants and U01 Clinical Trial
Implementation Cooperative Agreements
(http://www.niaid.nih.gov/ncn/clinical/R34.htm) offer the logical next step. Diagnostic
development should target demonstrable needs and should consider evaluation and
validation with appropriate clinical specimens. Research and product development
projects that address multiple agents such as broad spectrum therapeutics, novel drug
families, and multiplex diagnostics are particularly encouraged, especially when a clearly
demonstrable need is shown, and a pathway to clinical or field use is presented.
All applications should define the proposed project goal, describe the proposed final
product, and provide a schedule or timeline for goal attainment with measurable interim
objectives (essential milestones). A specific product profile defined by licensing
indication is not requested. When appropriate, research plans should demonstrate an
awareness of the guidelines that govern GLP (as defined by 21 CFR Part 58) and GMP
(as defined by 21 CFR Part 211) manufacturing, and/or IND/IDE enabling studies that
will be performed under this award as they would be applied to eventual product/device
licensure in the U.S.
The NIAID recognizes that critical aspects of the product development pathway such as
GLP, cGMP production, or diagnostic validations are not inherently innovative; however,
innovation is encouraged where it is appropriate to reduce project risk or to facilitate the
efficient accomplishment of goals.
Phase I, II, and III clinical trials and field trials are not supported by this RFA. However,
in the case of diagnostics, it is expected that appropriate human specimens will be used to
establish proof of principle, show that performance specifications can be met, to
demonstrate a level of utility that exceeds existing systems, and to clearly place the
proposed product on a pathway to FDA review. Collection of all specimens must comply
with the requirements and policies of 45 CFR Part 46, and the NIAID, DMID
(http://www.niaid.nih.gov/dmid/clinresearch/).
Therapeutics for Biodefense
Development of biodefense therapeutics is a key national priority. Applications are
invited that will lead to the development of therapies against Shiga toxins, ricin toxin, the
Staphylococcus enterotoxin B (SEB), Clostridium perfringens epsilon toxin and the
botulinum neurotoxins or the physiological insults that they cause. The NIAID
encourages the multidisciplinary collaboration and expertise of toxin researchers,
medicinal chemists, clinicians, and structural biologists needed to address discovery,
development, evaluation, and delivery of therapies.
Some of the challenges of developing post-exposure treatments for these toxins include
the following: toxin is free in the circulation for only a brief period of time (hours to
days); the therapeutic window for conventional anti-toxins (e.g., antibodies) that target
free toxin or block the binding of toxin to cellular receptors is short; and the patient is
asymptomatic prior to the intracellular internalization of the toxin. The greatest clinical
benefit would be derived from therapies capable of blocking or reversing either the action
of the toxin following cellular internalization or the host responses to the toxin that result
in disease.
Projects may include, but are not limited to, one or more of the following areas:
Identification, validation, or further study of drug targets either by examining the toxin,
or by examining and mitigating the effects of the toxin on the physiological and
immunological processes of the human host;
Performing studies such as molecular modeling, screening libraries, and medicinal
chemistry to rationally design and optimize candidate compounds for preclinical studies;
Exploration/extraction of the active components of natural products as potential sources
for drug development;
Development of new or improved animal models, or non-animal alternatives, required to
test candidate therapeutics, if appropriate and justified;
Pre-clinical development of novel therapeutic technologies including
immunotherapeutics, monoclonal antibodies, and siRNA;
Performing reiterative design, chemical synthesis and in vitro analysis to develop a lead
compound;
Optimization of lead compounds to improve the therapeutic activity, pharmacology, and
safety of the drug candidate;
Synthesizing, purifying, and testing sufficient quantities of lead compound(s) for efficacy
and toxicity studies in model assays and preclinical in vitro or in vivo models;
Performing preliminary pharmacokinetic and pharmacodynamic analyses;
assessing/optimizing bioavailability and mechanism of action;
Determining drug and metabolite interactions in host processes;
Process development for the manufacturing of drugs, including GLP and GMP, QA/QC,
methods for product recovery, characterization, purification, identity, stability, etc.;
Performing required benchmarks for successful submission and review of an IND
application by the FDA (http://www.fda.gov/cder/regulatory/default.htm), in preparation
for moving a drug candidate into Phase I clinical trials.
NOTE: Interventions that can block or reverse the effects of intoxication after the toxins
have reached their intracellular site(s) of action are of particular interest.
NOTE: For therapeutics development applications, of particular interest are projects that
incorporate formulation strategies that optimize the properties of the resulting product.
NOTE: Applications that do not address the development of a therapeutic or diagnostic
for Shiga toxins, ricin toxin, the Staphylococcus enterotoxin B (SEB), Clostridium
perfringens epsilon toxin or the botulinum neurotoxins will be deemed unresponsive and
will be returned to the applicant without review.
NOTE: Applications addressing therapeutics or diagnostics for the NIAID Category B
bacteria that produce Shiga toxins (diarrheagenic E. coli and Shigella) are not responsive
to this RFA, and should be directed to the companion solicitation (RFA AI-06-029,
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-06-029.html).
NOTE: Clinical trials will NOT be supported.
Diagnostics for Biodefense
There is an urgent need for easy to use, rapid, and cost-effective medical diagnostics for
public health laboratories, hospital-based clinical laboratories, field, and point-of-care use
to diagnose individuals exposed to and/or intoxicated with Shiga toxins, ricin toxin, the
Staphylococcus enterotoxin B (SEB), Clostridium perfringens epsilon toxin and the
botulinum neurotoxins. NIAID goals include supporting the development of diagnostics
that identify these toxins and instruct appropriate therapy for individuals who are presymptomatic, symptomatic, non-responding to treatment, or have non-specific symptoms.
The design and development of diagnostics should be focused on the steps critical to
product development and with an understanding of the clinical needs and the appropriate
sensitivity required for each toxin. Medical diagnostics that perform differential
diagnoses are of high priority. The development of medical diagnostics that use
multiplex, platform technologies is encouraged and can include other agents in addition
to Shiga toxins, ricin toxin, the Staphylococcus enterotoxin B (SEB), Clostridium
perfringens epsilon toxin or the botulinum neurotoxins, but must be focused on rapidly
distinguishing whether an individual is intoxicated with one of these toxins or by a
common disorder with similar, generalized symptoms. Projects may include, but are not
limited to, one or more of the following areas:
Technologies and assays that demonstrate the highest performance for their intended use
to detect toxins in relevant clinical samples (e.g., sensitivity, specificity, rapidity,
ruggedness, ease-of-use and cost-effectiveness);
Methods for rapid sample preparation, processing, and concentration;
Improved technologies, methodologies, and reagents for rapid, multiplexed diagnostics;
Technologies that integrate multiple methods of parallel measurements for detection in
the same platform, such as identifying nucleic acids, proteins, and other targets from
agents in the same assay;
Technologies targeting multiple biomarkers or signature profiles with high throughput
screening, to simultaneously identify multiple agents, and/or human immune or other
physiological responses during infection (e.g., platform-based technologies);
Methods capable of high throughput, robotic, and automated data output and analyses;
Process development for the manufacturing of diagnostic components, including QA/QC
methods for reagent recovery, characterization, purification, identity, and stability; and
Performing required benchmarks for successful submission and review of a 510(k) or
PMA application by the FDA (http://www.fda.gov/cdrh/index.html).
NOTE: Applications proposing the development of a diagnostic or therapeutic that do
not include Shiga toxins, ricin toxin, the Staphylococcus enterotoxin B (SEB),
Clostridium perfringens epsilon toxin or the botulinum neurotoxins will be deemed
unresponsive and will be returned to the applicant without review.
NOTE: This program will NOT support research on the development or deployment of
devices for the detection of agents in foods, fomites, or environmental specimens. Such
applications will be deemed unresponsive and returned to the applicant without peer
review.
NOTE: Applications addressing therapeutics or diagnostics for the NIAID Category B
bacteria that produce Shiga toxins (diarrheagenic E. coli and Shigella) are not responsive
to this RFA, and should be directed to the companion solicitation (RFA AI-06-029,
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-06-029.html).
See Section VIII, Other Information - Required Federal Citations, for policies related to
this announcement.