Key Dates

Related Announcements

PAR-19-040 - NIH Countermeasures Against Chemical Threats (CounterACT): Optimization of Therapeutic Lead Compounds (U01 Clinical Trial Optional)

Issued by

National Institute of Neurological Disorders and Stroke (NINDS)

National Eye Institute (NEI)

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

National Institute on Drug Abuse (NIDA)

National Institute of Environmental Health Sciences (NIEHS)

Purpose

The purpose of this notice is to add responsiveness criteria and to provide further clarification of the clinical trials permitted in Funding Opportunity Announcement (FOA) PAR-19-040, "Countermeasures Against Chemical Threats (CounterACT): Optimization of Therapeutic Lead Compounds (U01 Clinical Trial Optional)". This notice is intended to provide more guidance in developing grant applications that are more responsive to the scientific scope of the FOA.

The following sections of PAR-19-040 have been modified:

Currently Reads:

Part 2. Full Text of Announcement

Section I Funding Opportunity Announcement

F. Scientific Scope

This FOA will only support translational research. Translational research is the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of human disease. Projects supported by this translational research FOA are expected to generate sufficient preclinical data to deliver a single "Optimized Lead" candidate at the end of the funding period. More extensive advanced development support towards licensure could be available through other government, commercial, or non-profit sources. As described in the Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies, there are several kinds of studies and metrics that can lead to the selection of the "Optimized Lead" and these would depend on where in the optimization process you begin. The scope of research covered in this FOA can also be described by Technology Readiness Levels (TRLs). The TRLs covered in this FOA generally fall under TRLs 4 through 5.

Interested applicants without an already identified lead medical countermeasure should refer to the companion FOA "CounterACT Identification of Therapeutic Lead Compounds Cooperative Agreement (U01)" (PAR-19-039). Conversely, applicants interested in more advanced GLP IND-enabling drug research and development, cGMP manufacturing, and/or human safety clinical efforts with their lead therapy product should directly explore funding opportunities available through HHS BARDA Broad Agency Announcements.

To achieve the desired BARDA criteria listed in Section I.A., research covered in this FOA includes, but is not necessarily limited to:

• Determining acceptable pharmacokinetics (with a validated bioanalytical method)
• Non-GLP in vivo activity and potential for efficacy consistent with the product's intended use (i.e., dose, schedule, duration, route of administration, and route of threat agent challenge)
• Development of a stable and effective formulation
• Obtaining acceptable safety margin (toxicity in animal studies)
• Demonstrating feasibility of laboratory scale manufacturing
• Demonstrating an acceptable drug interaction profile

Important links to specific FDA Guidance and other regulatory information relevant to medical countermeasure research and development can be found under the FDA Guidance Documents section on the CounterACT website.

Examples of research covered in this FOA include, but are not necessarily limited to:

• Detailed understanding of the pathophysiological mechanism of toxicity of the threat chemical as it relates to the proposed indication of the previously identified lead candidate therapeutic
• Defining the mechanism of action of the lead candidate therapeutic that prevents or substantially reduces the toxic effects of the chemical threat, and a comparison of this mechanism of action between animal models being used and that in humans.
• Development of natural history animal models with primary outcomes that are predictive of lethality and/or serious morbidities caused by acute exposure to the chemical threat. This should include the natural history of the condition, time course of progression, and manifestation of the injuries to identify the trigger for intervention.
• Demonstrate efficacy in animal model more predictive of the human condition and more easily scalable in terms of therapeutic dose, e.g., swine, non-human primates, etc.
• In vivo dose-ranging and efficacy (non-GLP) studies against the chemical threat consistent with the product's intended therapeutic use regimen (i.e. dose, schedule, duration, route of administration, and route of threat agent challenge).The route and time(s) of administration of the therapeutic must be consistent with the intended use in humans, including the likely environment where the drug would be administered (pre-hospital or in-hospital settings).
• Development of assays, surrogate markers, correlates of protection, and endpoints to be used during non-clinical and clinical studies to further evaluate and characterize candidate(s)
• Chemical optimization of the lead to enhance target engagement, potency, stability, selectivity, specificity, bioavailability, metabolism, solubility, etc.,and/or to minimize predicted or previously encountered toxicity
• Selection and validation of the route of administration amenable for mass casualty care
• Analytical methods development and validation for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate
• Process optimization to allow for the manufacture of laboratory-scale (i.e. non-GMP) quantities of bulk product and proposed formulated product with the goal of developing a stable and scale-able manufacturing protocol amenable to GMP production
• Extending previously observed protective effect of the lead compound(s) for one chemical threat to others, i.e., broadening the spectrum of activity
• Study of alternate routes of administration and/or dosing regimen for the lead compound(s) that would be safer, more effective, or easier to administer during a mass casualty scenario or for specific vulnerable subpopulations (e.g., pediatric and pregnant)

Although clinical trials are optional in this FOA, NIH-defined clinical trials will only be supported under limited circumstances. This FOA will not support IND-enabling safety studies conducted under Good Laboratory Practices (GLP), pivotal efficacy studies in animals, cGMP production, or Phase 1 and higher trials in humans. However, in some rare cases when sufficient preclinical studies have been completed, a small clinical trial may be included if the proposed research falls within the above stated scientific scope of this FOA and is clearly justified as essential for the purpose of optimizing a lead compound. If clinical trials are proposed, they must be feasible within the proposed budget and project period.

Section IV: Application and Submission Information

7. Other Submission Requirements and Information

Important Reminders:

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Modified to Read (new language shown in italics):

Part 2. Full Text of Announcement

Section I Funding Opportunity Announcement

F. Scientific Scope

This FOA will only support translational research. Translational research is the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of human disease. Projects supported by this translational research FOA are expected to generate sufficient preclinical data to deliver a single "Optimized Lead" candidate at the end of the funding period. More extensive advanced development support towards licensure could be available through other government, commercial, or non-profit sources. As described in the Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies, there are several kinds of studies and metrics that can lead to the selection of the "Optimized Lead" and these would depend on where in the optimization process you begin. The scope of research covered in this FOA can also be described by Technology Readiness Levels (TRLs). The TRLs covered in this FOA generally fall under TRLs 4 through 5.

Interested applicants without an already identified lead medical countermeasure should refer to the companion FOA "CounterACT Identification of Therapeutic Lead Compounds Cooperative Agreement (U01)" (PAR-19-039). Conversely, applicants interested in more advanced GLP IND-enabling drug research and development, cGMP manufacturing, and/or human safety clinical efforts with their lead therapy product should directly explore funding opportunities available through HHS BARDA Broad Agency Announcements.

To achieve the desired BARDA criteria listed in Section I.A., research covered in this FOA includes, but is not necessarily limited to:

• Determining acceptable pharmacokinetics (with a validated bioanalytical method)
• Non-GLP in vivo activity and potential for efficacy consistent with the product's intended use (i.e., dose, schedule, duration, route of administration, and route of threat agent challenge)
• Development of a stable and effective formulation
• Obtaining acceptable safety margin (toxicity in animal studies)
• Demonstrating feasibility of laboratory scale manufacturing
• Demonstrating an acceptable drug interaction profile

Important links to specific FDA Guidance and other regulatory information relevant to medical countermeasure research and development can be found under the FDA Guidance Documents section on the CounterACT website.

Examples of research covered in this FOA include, but are not necessarily limited to:

• Detailed understanding of the pathophysiological mechanism of toxicity of the threat chemical as it relates to the proposed indication of the previously identified lead candidate therapeutic
• Defining the mechanism of action of the lead candidate therapeutic that prevents or substantially reduces the toxic effects of the chemical threat, and a comparison of this mechanism of action between animal models being used and that in humans.
• Development of natural history animal models with primary outcomes that are predictive of lethality and/or serious morbidities caused by acute exposure to the chemical threat. This should include the natural history of the condition, time course of progression, and manifestation of the injuries to identify the trigger for intervention.
• Demonstrate efficacy in animal model more predictive of the human condition and more easily scalable in terms of therapeutic dose, e.g., swine, non-human primates, etc.
• In vivo dose-ranging and efficacy (non-GLP) studies against the chemical threat consistent with the product's intended therapeutic use regimen (i.e. dose, schedule, duration, route of administration, and route of threat agent challenge).The route and time(s) of administration of the therapeutic must be consistent with the intended use in humans, including the likely environment where the drug would be administered (pre-hospital or in-hospital settings).
• Development of assays, surrogate markers, correlates of protection, and endpoints to be used during non-clinical and clinical studies to further evaluate and characterize candidate(s)
• Chemical optimization of the lead to enhance target engagement, potency, stability, selectivity, specificity, bioavailability, metabolism, solubility, etc.,and/or to minimize predicted or previously encountered toxicity
• Selection and validation of the route of administration amenable for mass casualty care
• Analytical methods development and validation for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate
• Process optimization to allow for the manufacture of laboratory-scale (i.e. non-GMP) quantities of bulk product and proposed formulated product with the goal of developing a stable and scale-able manufacturing protocol amenable to GMP production
• Extending previously observed protective effect of the lead compound(s) for one chemical threat to others, i.e., broadening the spectrum of activity.
• Study of alternate routes of administration and/or dosing regimen for the lead compound(s) that would be safer, more effective, or easier to administer during a mass casualty scenario or for specific vulnerable subpopulations (e.g., pediatric and pregnant)

Clinical Trial Information

Although clinical trials are optional in this FOA, NIH-defined clinical trials will only be supported under limited circumstances. In some rare cases when sufficient preclinical studies have been completed, a small clinical trial may be included if the proposed research falls within the above stated scientific scope of this FOA and is clearly justified as essential for the purpose of optimizing a lead compound. If clinical trials are proposed, they must be feasible within the proposed budget and project period.

For applications proposing a clinical trial, note the following definitions and restrictions for this funding announcement:

• Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. For this funding announcement, only the following type of clinical trial will be responsive to this FOA:
  • Mechanistic trials, defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., HOW an intervention works, but not IF it works or is safe).

Applicants are strongly encouraged to speak with the assigned Scientific/Research Contact prior to application.

• For further clarification on how NIH defines the different types of clinical trials, please refer to the following resources:
  • NOT-OD-15-015: Notice of Revised NIH Definition of “Clinical Trial”
  • NIH's Definition of a Clinical Trial
  • Decision Tree for NIH Clinical Trial Definition
  • NIH Definition of Clinical Trial Case Studies

Applications Non-Responsive to this FOA

• Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions.
• Delayed Onset Studies - A Delayed Onset Study is where research is anticipated within the period of award but definite plans are not yet known and cannot be described in the application (see https://grants.nih.gov/grants/glossary.htm#DelayedOnsetStudy).
• This FOA will not support IND-enabling safety studies conducted under Good Laboratory Practices (GLP), pivotal efficacy studies in animals, cGMP production, or Phase 1 and higher trials in humans.
• The objective of this FOA is the optimization of a pre-identified lead MCM candidate, where specificity, affinity, potency, target selectivity, post-exposure efficacy, and safety have already been established, by the end of the proposed project period. Pre-exposure/prophylaxis studies, including those proposed to demonstrate proof-of-principle bioactivity, will not be responsive to this FOA.

Section IV: Application and Submission Information

7. Other Submission Requirements and Information

Important Reminders:

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete or non-compliant will not be reviewed.

All other aspects of this FOA remain unchanged.

Inquiries

Please direct all inquiries to:

David A. Jett, Ph.D.
National Institute of Neurological Disorder and Stroke (NINDS)
Telephone: 301-768-9584
Email: [email protected]