TOPIC RELEASE 3.pdf

THE DEADLINE FOR INDUSTRY DAY REGISTRATION AND

CAPABILITY OVERVIEW SUBMISSIONS RELATED TO TOPICS

CBI-01 and CBS-02 IS FEBRUARY 12, 2021.

THE DEADLINE TO SUBMIT QUESTIONS RELATED TO ANY OF THE

FOLLOWING TOPICS IS MARCH 12, 2021.

THE PHASE I PROPOSAL SUBMISSION DEADLINE FOR ALL OF THE

FOLLOWING TOPICS IS APRIL 12, 2021 AT 2:00PM EASTERN

DAYLIGHT TIME (EDT).

Topic CBI-01

Advanced Capabilities for Chemical and Biological (CB) Human Health Effects Modeling

Background:

The deliberate release of a CB weapon on the battlefield poses a threat to the operational effectiveness of the Joint Force, impacting force readiness and lethality. In order to mitigate these negative impacts, decision support tools must provide timely and accurate estimates of the numbers of casualties and fatalities resulting from the incidental release and potential spread of CB agents in near real time.

The Joint Science and Technology Office (JSTO) Digital Battlespace Management Division is charged with researching and developing technologies to support the Chemical and Biological Defense Program. JSTO develops modeling and simulation tools to generate decision-oriented information and enable enhanced situational awareness with the goal of protecting military and civilian populations from intentional or incidental chemical or biological threat agents and Toxic Industrial Chemicals/Toxic Industrial Materials.

Objectives:

This topic supports the development of advanced human health effects modeling capabilities to produce high fidelity casualty estimates accounting for time varying and dose-dependent impacts from exposure to a CB threat agent. Model outputs should address both medically and operationally relevant health impacts to the Warfighter.

Proposed solutions should incorporate relevant experimental data and results from current studies.

Medically relevant inputs should account for parameters related to medical countermeasures (e.g., efficacy, pharmacokinetics/pharmacodynamics (PK/PD), treatment duration and length of protection), CB agent characteristics (e.g., toxicity, environmental fate, infectious dose), and human factors (e.g., respiratory dynamics, host immune responses), where possible. Operationally relevant outputs should quantify operational impacts affecting mission readiness and force lethality at different phases of the joint deployment and redeployment processes such as time to recovery, return to duty, risk to mission effectiveness and timeliness, and risk to force/unit strength.

Solutions that explore combined health effects resulting from exposure to chemical or biological threat agent mixtures will also be considered. Technical solutions should also be “turn-key” such that an end user could operate the software with a limited amount of training.

• Demonstrate compatibility with, and ability to operate within, the DTRA-developed Hazard Prediction and Assessment Capability (HPAC);

• Collaborate with HPAC development and integration team and other subject matter experts in regular integration meetings and Technical Exchange Meetings;

• Respond to HPAC Software Product Change Requests (SPCRs);

• Integrate seamlessly with other CB software platforms or non-HPAC source code as required [e.g., Tactical Assault Kit (TAK) variants, Joint Medical Planning Tool (JMPT)];

• Implement Agile software development processes;

• Provide automation for default standards, but also allow flexibility for end user to manually change input parameters to support course of action analyses based on evolving information as required.

Preference will be given to offerors who address both medically and operationally relevant health parameters and propose a multi-disciplinary team composed of subject matter experts in fields including, but not limited to, modeling and simulation, statistics, infectious disease epidemiology, microbiology, virology, pharmacology, toxicology, immunology, etc.

Software Considerations:

Proposed software solutions should adhere to the following requirements:

• Software must be fully documented and easy to access, modify, and extend;

• Software must comply with DoD standards for authorization to operate;

• Software should not require recurring license fees;

• Software should be able to run on a variety of DoD approved end user computing devices [(e.g., PCs, Virtual Machines)];

• Software must be tested, verified, and maintained.

Impact:

This topic will support joint force health protection by developing advanced health and human effects modeling capabilities to provide higher fidelity casualty estimates and health effects predictions in support of military medical planning for, and operational readiness against, new and emerging CB battlefield threats.

Industry Day:

Interested parties are invited to attend an Industry Day prior to submission of Phase I proposals. The Industry Day offers an opportunity to hear an overview of the topic, seek clarification on the objectives, and hear additional context on goals and expectations. Participation in Industry Day is not mandatory and questions and answers from the event will be posted to beta.SAM.gov. Details and registration can be found via: https://cvent.me/yqMRBN.

References:

Department of Defense. (2018) Chemical and Biological Defense 2018 Annual Report to Congress.

Washington, D. C.: DoD.

White House. (2018). National Biodefense Strategy 2018. Washington D.C.:

https://www.whitehouse.gov/wp-content/uploads/2018/09/National-Biodefense-Strategy.pdf

Department of Defense. (2008). DoD CBRN Defense: Doctrine, Training, Leadership, and Education Strategic Plan. Washington, D. C.: CBDP.

Naval Medical Research and Development. Modern Tools for Modern Medical Planning (2017) https://www.med.navy.mil/sites/nmrc/sitepages/NewsStory.aspx?StoryID=293

Wood RM, Egan JR, Hall IM. 2014 A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application to Francisella tularensis. J.RSoc.

Interface 11: 20140119. http://dx.doi.org/10.1098/rsif.20140119 https://cvent.me/yqMRBN http://dx.doi.org/10.1098/rsif.20140119

CBS Topic-01

Validated Strategies for Evaluation of Products for Treatment of Chemically-Contaminated Wounds

Background:

Chemical warfare agents (CWAs) are among the most deadly weapons of mass destruction (WMD) known. The most significant classes of CWA include nerve agents such as VX and sarin, vesicants including sulfur mustard, and pharmaceutical-based agents such as fentanyl.

The management of casualties with exposures to CWAs is well documented since the first battlefield use of chemical weapons in World War I (WWI). Medical management has evolved from supportive care only to the development of specific therapeutic countermeasures. This approach has been successful in providing targeted solutions in both the prevention and the treatment of insult or injury from many CWAs. These medical chemical countermeasures include the Antidote Treatment Nerve Agent Autoinjector (ATNAA) used to treat personnel exposed to the agent, and Reactive Skin Decontamination Lotion (RSDL), a lotion designed for spot decontamination to remove and neutralize CWAs on the skin.

However, battlefields may be contested with the use of chemical and biological agents along with conventional tactics. Thus, combat casualties may experience combined traumatic injuries and chemical contamination. Because of this, there are active efforts to develop the capability to treat vulnerable areas such as traumatized tissues and the eye for contamination with CWAs.

There is not currently a standardized strategy for evaluation of novel wound decontamination products.

An ideal strategy would hierarchically assess products through increasingly stringent and informative models, with decision gates and criteria for efficient elimination of unsuccessful candidate products. It would provide a uniform overall process for assessment of diverse decontamination products, with consistent assays and endpoints to facilitate comparisons of different products evaluated in different laboratories. The models used, whether in silico, in vitro, ex vivo, or in vivo, would be validated and would provide safety and efficacy data to support decision making and product down selection. Data from such a system would be supportive of US Food and Drug Administration (FDA) review for licensure of candidate products.

Objective:

DTRA seeks proposals for developing and validating a strategy for evaluation of wound decontamination products. Based on this work, any qualified and capable laboratory should be able to use the product evaluation strategy to test and evaluate wound decontamination candidate products. Results of the assessments will provide consistent and accurate indications of the products’ safety and efficacy. Users of the strategy will be able to make clear and correct evidence-based decisions about which products to develop further. Critical questions will be addressed at the earliest possible stages, for efficient decision-making. Data generated in the course of the evaluation will be directly relevant to the regulatory pathways for candidate products, and will be suitable for submission to the FDA in support of market approval or licensure for human use.

We expect a variety of tools to be considered for use in addressing the requirement, including in silico, in vitro, ex vivo, or in vivo systems, possibly including established models as well as development of novel approaches if needed. Those proposing in vivo models should address how development of the model and the data generated in the proposed effort would support seeking FDA Animal Model Qualification for wound decontamination products (https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp). Standardized data formats supportive of sophisticated modeling and machine learning are desirable, as are organ-on-a-chip or other approaches https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp that appropriately reduce time and animal use requirements. The use of surrogates for CWAs vs. CWAs themselves over the course of the evaluation strategy should be carefully weighed to optimize cost and convenience of the assessment vs. the relevance of the results to the intended use in the treatment of CWA-contaminated wounds.

Offerors are encouraged to develop R&D collaborations with other organizations in Government, academia, and the private sector to broaden and strengthen their knowledge, experience and capabilities.

Additionally, offerors are encouraged to take advantage of specialized resources in DoD and other Government agencies such as facilities/capabilities with chemical surety certification, and for non-GLP preclinical studies, ADME (Absorption, Distribution, Metabolism, and Excretion) testing and manufacturing. If applicable, it is encouraged that engagement with the FDA be pursued throughout the contract.

Types of proposals that do not meet the intent of this topic include those that only propose specific model(s) but do not integrate them into an evaluation and decision process, and those that have proprietary elements or other barriers to widespread use and comparison of diverse chemical and biological countermeasure products. Such proposals will not be evaluated further.

Impact:

The results of proposed research efforts will ultimately provide the Warfighter with rapid and effective development of chemical medical countermeasures that can be used in chemically contaminated wounds.

This product development pipeline will support efficient and nimble development of new wound decontamination solutions.

References:

1. Food and Drug Administration (FDA), (2015). Product Development under the Animal Rule FDA Guidance: https://www.fda.gov/downloads/drugs/guidances/ucm399217.pdf

2. Hughes, M. et al., (2014), “Early drug discovery and development guidelines: for academic researchers, collaborators, and start-up companies” Assay Guidance Manual [Internet], May 1.

PMID: 22553881.

3. U.S. Health and Human Services (U.S. HHS). U.S. HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) TRLs:

https://medicalcountermeasures.gov/trl/integrated-trls

4. Food and Drug Administration (FDA). FDA Animal Model Qualification Program:

https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp https://www.fda.gov/downloads/drugs/guidances/ucm399217.pdf https://medicalcountermeasures.gov/trl/integrated-trls https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/animal-model-qualification-program-amqp

Topic CBS-02

Innovative Approaches for Improving Drug Delivery to the Central Nervous System to Better Counter Nerve Agents

Background:

Chemical warfare agents (CWA) are among the most deadly weapons of mass destruction (WMD) known. Significant classes of CWA include organophosphate nerve agents (OPNA) such as soman, VX, sarin and Novichoks. OPNAs act by inhibition of acetylcholinesterase (AChE) resulting in reduced hydrolysis of the neurotransmitter, acetylcholine. Accumulation of acetylcholine causes overstimulation of the acetylcholine receptor. Physiological responses to OPNA exposure include hypotension, rhinorrhea, wheezing and diarrhea. Significant exposure to OPNA may be fatal. As a result, OPNA poses a significant threat to military forces.

Current antidotes include charged oximes that are capable of reactivating AChE after its inactivation by OPNA. Although pralidoxime (2-pyridine aldoxime methyl chloride [2-PAM]), the FDA-approved AChE oxime reactivator, reactivates AChE in the periphery, it does not efficiently cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), which is an important site of OPNA toxicity. Further limiting its utility, the spectrum of 2-PAM is relatively narrow and is not effective against the full range of OPNAs.

OPNAs can reach and have longer-term effects on the CNS. Current reactivator countermeasures do not efficiently cross the BBB. This shortcoming creates a significant treatment gap. As a result, improving CNS delivery of current nerve agent therapeutics with proven in vivo efficacy would be useful in treating OPNA-exposed individuals. It is hypothesized that such a therapeutic could increase survival, hasten return to duty and potentially ameliorate the acute and longer-term effects of OPNAs on CNS function.

Since delivery of therapeutics to the CNS is an active area of research in the pharmaceutical industry, harnessing advances in existing trans-BBB delivery technologies for the delivery of small molecule countermeasures would be beneficial.

Objective:

Proposals are sought for drug delivery technologies that improve the BBB permeability of 2- PAM in order to treat OPNA exposure within the CNS. Technologies in all stages of drug development will be considered, from drug discovery and novel approaches through Phase I clinical trials. Later stage delivery technologies/platforms will have priority over novel approaches not yet tested in the clinic.

Areas of research that will not receive consideration under this topic include proteins or enzymatic processes designed to remove nerve agent from circulation, acetylcholine receptor inhibitors, AChE inhibitors, new anticonvulsants, gamma-aminobutyric acid or glutamate receptor modulators, and/or the use of reactivators other than 2-PAM.

Strategies may target active or passive transport mechanisms and may include, but are not limited to, the following:

• Nanoencapsulation1, such as:

o Dendrimers o Liposomes o Carbon nanotubes o Polymeric micelles

• Pharmaco-chemical strategies (i.e., making a drug more lipophilic) such as:

o Genetic engineering o Drug conjugates

Delivery technologies that focus on delivering 2-PAM to the CNS are preferred. Proposals should detail past or current clinical testing or use of the strategy. Research programs spanning the drug development process up to Phase 1 clinical trials (TRL6) may be appropriate. Regardless of program maturity, offerors should propose milestone driven projects. R&D collaborations with other organizations within the Government, academia, and the private sector are acceptable.

The following attributes should be considered to develop the most attractive proposal:

1. Medical Countermeasure (MCM) candidates which demonstrate compatibility with military operations, for example in terms of ease of administration, storage stability, and minimal number of administrations to provide desired protection

2. Potential side effects of MCM

3. MCM with broad spectrum application across a wide spectrum of OPNA

4. MCM that are able to penetrate the BBB

5. Demonstration of previous clinical testing/use or safety of the delivery technology

6. Minimal cost per dose

7. MCM allowing for repeat administration with limited immunogenicity

8. Fully developed comprehensive TPP and regulatory strategy, appropriate to program maturity

9. Preliminary data supportive of proof-of-concept

Impact:

The results of the proposed research efforts will ultimately provide the Chemical and Biological Defense Program with novel MCM technology for the treatment of the adverse effects associated with a range of OPNA in the CNS. This product will allow for acute care on the battlefield and will prevent neurodegeneration, promoting an enhanced quality of life for OPNA-afflicted Warfighters.

Industry Day:

Interested parties are invited to attend an Industry Day prior to submission of Phase I proposals. The Industry Day offers an opportunity to hear an overview of the topic, seek clarification on the objectives, and hear additional context on goals and expectations. Participation in Industry Day is not mandatory and questions and answers from the event will be posted to beta.SAM.gov. Details and registration can be found via: https://cvent.me/yqMRBN.

References:

1. Naqvi, S., Panghal, A., & S.J.S. Flora. (2020). Nanotechnology: A promising approach for delivery of neuroprotective drugs. Front. Neurosci. 14:494. PMID: 32581676

2. U.S. Health and Human Services (U.S. HHS), U.S. HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) TRLs:

https://medicalcountermeasures.gov/trl/integrated-trls https://cvent.me/yqMRBN

Topic CBS-03

Identifying and Developing Natural Product-based Medical Countermeasures to Prevent or Treat the Adverse Effects of CWA Exposure

Background:

The management of casualties with exposures to chemical warfare agents (CWAs) is well documented since the first battlefield use of chemical weapons in World War I (WWI). In the century since WWI, Western science has invested a significant amount of time and money in the area of pharmaceutical development and has been successful in providing targeted solutions in the prevention and treatment of insult or injury from many CWAs. However, in order to achieve a rapid response to emerging chemical threats and manage the risks of technology development enabling surprise from new threats, the development of adaptive and flexible medical countermeasures (MCMs) for both prophylaxes and therapeutics is needed.

While modern pharmaceutical developmental approaches have provided significant improvements for the treatment of chemical casualties, naturally occurring remedies like plant-based, microbially-derived, and naturally occurring venom-based products may provide alternative approaches to MCM development.

When used either exclusively or in combination with conventional Western medicine, the use of traditional medicine, ethnobotanical approaches (e.g. Chinese medicine, Ayurvedic medicine, etc.), or other naturally occurring products could provide a broader approach to treating an individual’s response to chemical insult.

Objective:

This topic seeks to identify natural products and/or natural-product-based pharmacophores that may prevent or treat the adverse effects of chemicals that produce either the Cholinergic or Convulsant Toxidromes such as those caused by organophosphate nerve agents (OPNAs) (https://chemm.nlm.nih.gov/toxicsyndromes.htm). Proposals are sought for projects to identify and/or investigate natural products and/or natural product-based pharmacophores, preferably 1) those that have been previously demonstrated to have beneficial applications in traditional medicine or other clinical settings, and 2) those that seek to demonstrate at least proof-of-concept efficacy and safety in appropriate in silico, in vitro, ex vivo and/or in vivo models. Proposals with more advanced candidate MCMs may plan to move through the later stages of the drug development pipeline (up to Phase I clinical trials).

Proposals are sought for novel and innovative therapeutic MCMs to protect against chemicals that cause either the Cholinergic or Convulsant Toxidromes. MCMs in all stages of drug development will be considered, from drug discovery through Phase I clinical trials. Areas of research that consider repurposing and reformulation of FDA approved, late-development, or failed candidates for other indications are of interest as well. Preliminary data to support proof-of-concept will be considered favorably. Later stage candidates will have priority over novel approaches not yet tested in the clinic.

White papers should include research plans that address proof of safety and efficacy. Proof of efficacy should use quantitative metrics such as decrease in seizure activity, decrease in secretions, increase in time to symptom onset, increase in survival time, increase in ID50, ED50 or LD50 of the toxicant, etc.

Research plans should also address whether or not this is a single molecule or a natural extract that may be a mixture of multiple chemical entities.

If the proposal includes developing a candidate MCM up to or past technology readiness level (TRL) 3C, it will be required to demonstrate the in vivo activity of candidate(s) to counteract the effects of the threat agent / toxicant. (https://medicalcountermeasures.gov/trl/integrated-trls) https://chemm.nlm.nih.gov/toxicsyndromes.htm

Areas of research that will not receive consideration under this topic include:

• Research using Schedule 1 drugs or related compounds

• Research using natural products that produce the same effects as Schedule 1 drugs,

• Research with products from endangered plant or animal species

• Research of compounds that have been invested in by DTRA, NIH CounterACT, JPEO CBD, BARDA or others doing chemical weapons agent medical countermeasure development (e.g.

scopolamine, galantamine, huperzine, etc.)

The following attributes should be considered to develop the most attractive proposal:

1. Medical Countermeasure (MCM) candidates which demonstrate compatibility with military operations, such as ease of administration, storage stability, and minimal number of administrations to provide desired protection

2. Potential side effects of MCM

3. Demonstration of previous clinical testing/use or safety of the delivery technology

4. MCM with broad spectrum application across a wide spectrum of CWAs

5. Minimal cost per dose

6. MCM allowing for repeat administration with limited immunogenicity

7. Fully developed comprehensive TPP and regulatory strategy, appropriate to program maturity

8. Preliminary data supportive of proof-of-concept

Impact:

The results of proposed research efforts will ultimately provide the Warfighter and the Chemical and Biological Defense Program with a more agile and robust discovery and development pipeline for chemical medical countermeasures. Additionally, it will provide improved protection against and treatment for the adverse effects of the Cholinergic and/or Convulsant Toxidromes and the agents that cause them. Furthermore, this research will provide risk reduction to the current candidates in the pipeline for both the early and advanced developers.

References:

1. U.S. Health and Human Services (U.S. HHS), U.S. HHS Chemical Hazards Emergency Medical Management (CHEMM) https://chemm.nlm.nih.gov/toxicsyndromes.htm

2. U.S. Health and Human Services (U.S. HHS), U.S. HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) TRLs:

https://chemm.nlm.nih.gov/toxicsyndromes.htm

References: