HR001120S0015.pdf

Broad Agency Announcement Personalized Protective Biosystem (PPB)

BIOLOGICAL TECHNOLOGIES OFFICE

HR001120S0015

November 26, 2019

HR001120S0015, PPB

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. Program Overview

1.2. Technical Areas

1.3. Technical Approach

1.4. Program Schedule, Milestones & Metrics

1.5. General Requirements

2. Award Information

2.1. General Award Information

2.2. Fundamental Research

3. Eligibility Information

3.1. Eligible Applicants

3.2. Organizational Conflicts of Interest

3.3. Cost Sharing/Matching

4. Application and Submission Information

4.1. Address to Request Application Package

4.2. Content and Form of Application Submission

Disclosure of Information and Compliance with Safeguarding Covered Defense Information Controls

4.3. Funding Restrictions

4.4. Other Submission Information

5. Application Review Information

5.1. Evaluation Criteria

5.2. Review of Proposals

6. Award Administration Information

6.1. Selection Notices

6.2. Administrative and National Policy Requirements

6.3. Reporting

6.4. Electronic Systems

7. Agency Contacts

8. Other Information

9. APPENDIX 1 – Volume II checklist

PART I: OVERVIEW INFORMATION

Federal Agency Name – Defense Advanced Research Projects Agency (DARPA), Biological Technologies Office (BTO)

Funding Opportunity Title – Personalized Protective Biosystem (PPB) Announcement Type – Initial Announcement Funding Opportunity Number – HR001120S0015 North American Industry Classification System (NAICS) – 541714 Catalog of Federal Domestic Assistance Numbers (CFDA) – 12.910 Research and

Technology Development Dates o Posting Date: November 26, 2019 o Proposal Abstract Due Date and Time: January 7, 2020, 4:00 PM ET o Full Proposal Due Date and Time: February 20, 2020, 4:00 PM ET o BAA Closing Date: February 20, 2020 o Proposers’ Day: December 4, 2019

DARPA-SN-20-10 on beta.SAM.gov

Concise description of the funding opportunity – The Personalized Protective Biosystem (PPB) program will develop an integrated ensemble that simultaneously reduces protective equipment needs while increasing protection for the individual against existing and future chemical and biological (CB) threats. The capability to provide unburdened CB protection will maximize time on target for the warfighter and the stability operator, provide operational flexibility, extend mission duration, and enable military operations in austere environments regardless of the threat. PPB will consist of lightweight materials that protect the warfighter from exposure to any CB threat while simultaneously providing a second layer of protection, at the tissue barrier, with bio-molecular, commensal organisms, or other technologies that protect the skin, eyes, and airway from CB threats. PPB will improve mission execution by solving the current (“state of the art”) protective equipment limitations, including threat-specific vulnerabilities, thermal/logistical burdens, exposure risks during equipment removal/decontamination, and on-demand availability during unexpected threat situations.

Anticipated individual awards – Multiple awards are anticipated.

Types of instruments that may be awarded – Procurement contract or Other

Transaction.

Agency contact

The BAA Coordinator for this effort may be reached at:

PPB@darpa.mil

DARPA/BTO

ATTN: HR001120S0015

675 North Randolph Street Arlington, VA 22203-2114 https://beta.sam.gov/opp/aa352a86301049509d021353e6ae7431/view?keywords=DARPA-SN-20-10 mailto:PPB@darpa.mil

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

This publication constitutes a Broad Agency Announcement (BAA) as contemplated in Federal Acquisition Regulation (FAR) 6.102(d)(2) and 35.016. Any resultant award negotiations will follow all pertinent law and regulation, and any negotiations and/or awards for procurement contracts will use procedures under FAR 15.4, Contract Pricing, as specified in the BAA.

The Defense Advanced Research Projects Agency (DARPA) often selects its research efforts through the Broad Agency Announcement (BAA) process. The BAA will appear first on the Beta.SAM.Gov website, https://beta.sam.gov. The following information is for those wishing to respond to the BAA.

The Defense Advanced Research Projects Agency (DARPA) is soliciting innovative proposals to address the following areas: (1) novel textiles that prevent chemical and biological (CB) agent access to the body; and (2) a tissue barrier countermeasure (BCM) that neutralizes CB agents should they come in contact with the skin, airway, or eyes. Proposed research should investigate approaches that enable revolutionary advances in the development of wearable, lightweight, and smart materials that resist CB agent penetration/attachment. The goal for the PPB ensemble is to remain effective for deployments of up to 30 days and provide on-demand CB protection formissions of up to 12 hours at any time within the 30-day window. The BCM component should utilize host-compatible and high-efficiency protection strategies such as: chemical and biological agent-degrading enzymes, reconfigurable/robust expression chassis with commensal organisms, or highly stable biological nanoparticles. To administer BCM technologies, performers should develop delivery methods that can be self-administered from hand-held devices. The Personalized Protective Biosystem (PPB) will provide on-demand, broad-spectrum protection that can evolve at the pace of emerging threats.

The protective products currently in use, biological or otherwise, focus on one-threat countered by one-countermeasure, are not intrinsically adaptable, and rely on bulky, thick materials with respirators/ocular protection for sensitive tissue barrier protection. The PPB program will provide a dynamic response to multiple threats in a way that takes cues from natural systems capable of protecting against a diverse array of threats. For example, shark skin’s inherent anti-fouling capabilities can be harnessed by mimicking the shark skin-texture on a wide variety of materials for antimicrobial applications. Further, bacterial communities that currently live in the human body can sense and respond, protecting against environmental bacterial and fungal infection. Molecular, nano, and other material solutions, when coupled with lessons from natural systems, will be integral for PPB technologies to protect against current and future CB threats.

1.1. PROGRAM OVERVIEW

The goal of the PPB program is to develop an integrated ensemble that simultaneously eliminates protective equipment needs while increasing protection for the individual against all CB threats.

The capability to provide unburdened CB protection will reduce the logistical burden on the warfighter, provide operational flexibility, and sustain military operations in remote theaters, which may include diverse, unpredictable, and unknown threats.

https://beta.sam.gov/

The current CB threat environment consists of broadly acting, highly pathogenic, and sometimes immediately lethal threats that are capable of entering the body via multiple pathways, including skin, airway, ocular, and the gastrointestinal tract. Despite substantial financial investments and advances in the CB Defense enterprise over many decades, current personal protective equipment (PPE) solutions add logistical, mobility, and thermal challenges to the warfighter/stability operations care provider, which place their missions at risk. For example, typical PPE consists of cumbersome suits and respirators that require assistance and infrastructure for proper donning and doffing, and decontamination procedures to avoid contamination from agents that may still be present on the PPE. In a humanitarian assistance setting, the hours needed to don, doff, and decontaminate PPE leaves roughly two hours in an eight hour work day for a care provider to spend with patients, as seen in the Ebola 2014 (West Africa) and 2017 (Congo) outbreaks. These procedures limit the efficacy of stability operations workers in pandemic outbreak scenarios. Even with standard decontamination procedures and protective measures in place, hundreds of care providers have been infected with life-threatening biological agents, ranging from Ebola to Tuberculosis, due to PPE failures. In a military context, standard military PPE constrains vision, mobility, and “time on target,” thereby negatively impacting warfighter lethality. Moreover, PPE is not instantaneously available for individuals operating in austere or poorly resourced environments with no logistics infrastructure. Finally, current PPE is not designed with a robust second line of defense, should the outer layer(s) fail.

Current, second-line technology includes topical treatments that are applied after agent exposure or that simply block but do not neutralize threat agents during exposure; these treatments are not designed to work in concert with existing PPE. Rather, the state-of-the-art strategy has been to build thicker, heavier, and more logistically burdensome PPE.

The PPB program is directed at providing a two-part solution to support the individual in the following operational scenarios: (a) mission execution with minimal to zero logistical footprint, while engaging in an unanticipated multiplexed threat environments; and (b) humanitarian assistance and disaster relief (HADR) during pathogenic outbreaks in austere environments without logistical support.

The PPB program envisions two technical areas (TAs) for development under this BAA. From the outset, proposed approaches and developed technologies should identify outputs that align to both Technical Area 1 (TA1) and Technical Area 2 (TA2) as described in Figure 1. TA1 technologies will prevent contact between the body and CB agents using protective, smart materials with near-zero logistical burden. TA2 technologies will neutralize threats at vulnerable tissue barriers using a configurable BCM.

Figure 1 Schematic of PPB program objectives

By program completion, PPB platforms should be capable of immediately protecting the operator against multiple CB agents (see Program Milestones, Metrics and Schedule for specific details). Technologies should function in austere and/or isolated environments (e.g., far forward positions with limited infrastructure) for prolonged deployments of up to 30 days.

Revolutionary approaches directed at increasing CB protection while unburdening the operator will be necessary to accomplish the program goals. PPB platforms should be tested iteratively and optimized against various threat challenges with increasing complexity and performance requirements as the program progresses. Testing protocols will be developed to place the PPB ensemble on a path towards clinical translation and regulatory approval. Performers will be expected to attain Food and Drug Administration (FDA) Investigational New Drug (IND) approval by the end of the program for relevant PPB components. Further, performers will be required to engage with the FDA and other regulatory groups for design guidance on day one of the program.

1.2. TECHNICAL AREAS

The PPB program is structured as a five (5) year effort consisting of three (3) phases: (Phase I (Base), Phase II (Option One), and Phase III (Option Two)).

As designs will be heavily influenced by testing results, a significant investment has been made by DARPA to support an Independent Verification and Validation (IV&V) testing infrastructure that will enable an iterative developmental approach for the performers detailed further in the “PPB Testing” section.

Proposed efforts must describe a plan to address both of the TAs over the entire program duration (60 months). At the end of the program, performers will have developed a PPB ensemble capable of providing 100% survival against lethal exposure from 11 separate chemical and biological agents (10 for TA1, and 5 (4 of which overlap with TA1) for TA2, Table 1).

Tables 2 and 3 describe the schedule of evaluations and program assessment events that will drive programmatic decisions throughout the program.

The technical areas are described below:

TA1 Prevent contact: Performers will develop materials that, when applied or worn, prevent the wearer from coming in contact with CB threats, while reducing donning processes to less than 10 minutes to provide full body coverage. Additionally, these TA1 technologies will be available to the warfighter or stability operations operator with near-zero logistical burden (e.g., no respirator, contamination-free donning and doffing). Further, accidental cross-contamination should be eliminated by the material’s ability to inactivate, sequester, and/or eliminate attachment of agents.

TA2 Neutralize threats at tissue barriers: This technical area will neutralize agent at one or all of the potential airway, ocular, or skin interfaces, as necessary, to protect against agent exposure. This will supplement TA1’s protective barrier by providing persistent, offsetting, and orthogonal protection against threats that may penetrate the outer layer material or contact the wearer during doffing procedures. Newly adapted BCM technologies must increase CB protection breadth and specificity without sacrificing the protection against the original catalog of CB agents.

Teams must propose to both TA1 and TA2. Fully integrated teams should be assembled early in the proposal process, and the integration of both scientific and managerial responsibilities should be conveyed in the submission. Integrated teams should describe the organizational structure within the team, complete with a dedicated project manager (separate from the principal investigator) to show distribution of responsibilities, lines of communication, and technical tasks throughout the proposal. Teams should structure themselves to support continuous, active engagement with regulatory agencies to ensure a path towards clinical translation and regulatory application approvals such as IND or Emergency Use Authorization (EUA) as appropriate.

1.3. TECHNICAL APPROACH

Technical Area 1 (TA1): Prevent Contact TA1 objectives must be achieved using technologies that prevent agent access to the wearer by blocking, degrading, or otherwise sequestering agent away from the body while also eliminating active agent binding on the material itself post-exposure. Materials that may accomplish this goal might include enzymatic, molecular, nanopore, or other technology and material combinations.

Regardless of approaches proposed, the performers must specify the anticipated dynamic range of protection across threat concentrations and environmental conditions in their proposals. The ability to protect against large “mass-action” effects (at levels equal to or in excess of lethal doses) when large quantities of agent are encountered is a critical feature of the TA1 component.

Materials or barriers requiring application of active coatings should be long lasting, durable, and weather resistant. TA1 materials should be lightweight and impose negligible thermal burden or mobility restriction in relation to work rate, duration, or environmental considerations. Garment engineering approaches should consider use in austere and low-infrastructure environments as part of the initial design constraints. Detailed design goals for TA1 are below (further details and specific metrics can be found in Tables 2, 3) and should be achieved by the end of the program:

Protect against a broad spectrum (Table 1) of CB threats simultaneously with no impact on mission execution and time on target when compared to operators who do the same tasks without protective materials.

Insignificant logistical or thermal burden during normal military or patient care operations.

Protective materials developed should have evaporative resistance and permeability consistent with current military duty uniforms, such as the Army Combat Uniform

(ACU).

Material technologies will have physical performance equivalent to standard-issue military uniforms across all operating conditions to include extreme temperatures, precipitation, humidity, and other environmental scenarios (high dust or other environmental particulates).

Solutions should innovate above standard hydrostatic resistance performance of waterproof fabrics.

Reduce agent attachment to limit exposure risk during donning/doffing.

Durability should exceed the performance criteria of current military duty uniforms (such as the ACU) relative to impact abrasion, seam burst strength, and impact cut resistance.

Rapid don/doff, while also eliminating the risk of contamination to the wearer from incidental exposure to any agent that may have remained on the TA1 components.

System should withstand usage (including repeated donning/doffing) for the entire duration of any deployment.

The system as an ensemble of multiple garments, or as one continuous material should be lightweight, offering protection to the entire head, body, and extremities.

The IV&V team will administer tests as described below in Phase I and Phase II, culminating in key TA1 program milestones, metrics, and program assessment events (Tables 2, 3).

Technical Area 2 (TA2): Neutralize Threats at Tissue Barriers

TA2 is focused on the innovation and development of a BCM that neutralizes multiple threats encountered by vulnerable tissue barriers (ocular, respiratory, dermal). Proposers should submit potential solutions to neutralizing agent at airway, eye, and skin vulnerabilities, with the end goal of ensuring 100% protection in preclinical models against agents listed in Table 1. BCM will (a) provide simultaneous protection against diverse CB agents; (b) have the ability to add protection against novel threats (as they emerge) to the original catalog of threat protection; (c) be enabled by commensal, synthetic biological and/or nanoparticle-based components; and (d) possess multiple user-controlled safeguards (on/off capability). Proposers should develop innovative approaches to counter CB threats using high-throughput, scalable, molecular and biological production methodologies. Proposals should also describe solutions to TA2 that are allogeneic.

Successful completion of TA2 milestones and metrics will yield a BCM platform capability that can provide on-demand, rapid, and adaptable protection at tissue barriers. Newly adapted BCM platforms will increase CB protection breadth and specificity without sacrificing the protection against the original catalog of CB agents. The list below summarizes the primary design goals for the TA2 BCM, with specific metrics detailed in Tables 2 and 3:

Neutralize against a broad spectrum (Table 1) of CB threats simultaneously at vulnerable tissue barriers (protecting ocular, respiratory, dermal).

Contain safeguards, such as an on/off switch, that can be used to personalize the duration of protection and be deactivated with user-administered treatments that are non-toxic and FDA-cleared.

o BCM’s built-in responsive capability should provide two immediate benefits: (1) serve as a proactive tool to enhance the safety of BCM for the end user, and (2) provide on-demand and personalized temporal protection.

Adapt the system to add protection against new threats without compromising existing breadth of protection.

Platforms that are shelf-stable (for up to 2 years) without cold chain at room temperature at standard temperature and pressure (STP), mass produced in a Good Manufacturing Practices (GMP) setting, and able to obtain FDA clearance for a self-administered, hand-held device (e.g., eye-dropper, inhaler).

Platforms that provide ease of delivery, safety, rapid activation, and long lasting protection.

Proposed protection system(s) and approach(es), including the details for living or non-living solutions and the method(s) mediating protection, are required. The list below summarizes the potential details proposers should address in their proposal as it relates to their specific TA2 solution:

a) Platform(s) to be used such as: nanoparticles, biologics, small molecules, bacteria, fungi, protozoa, metazoa, virus, biologics, etc.

b) Dose per kg body weight in terms of: mass of compound, total particles, colony forming units (CFU), propagules, parasitic burden, active units, viral particles, etc.

c) Dynamic range and associated pharmacokinetics/pharmacodynamics of platform-mediated countermeasure production, if the platform actively produces countermeasures

d) Safeguards, i.e., on/off regulation of countermeasure expression, maintenance and or clearance of chassis from operator.

e) Platform delivery mechanism and residual anatomical localization, i.e., systemic, tissue, organ specific retention.

f) Characteristics of platform residence time. Define if, when, rate of platform shedding/clearance, and transmission mitigation strategies as appropriate.

It is critical that proposers provide a solution that results in zero injury, toxicity, immunogenicity, or other adverse effects to the host.

PPB Testing

The first 24 months of the program are designed as a Design-Test-Refine strategy, organized for teams to develop and evaluate PPB design approaches and enable the teams to iteratively improve their approaches. Teams will have the opportunity to conduct feasibility studies and tests in collaboration with the IV&V team during the first 18 months. These evaluations are not considered downselection events. Rather, these evaluations are considered opportunities for performer teams to iteratively refine technology prior to the 24-month Protection and Adaptation IV&V testing milestone (Figure 2, Phase 1).

Prior to 24 months proposer teams are encouraged to prepare for success by actively engaging PPB IV&V teams, co-developing testing methodologies, and performing in-house or outside facility testing of numerous design prototypes proactively defining ranges of protection and failure. Lastly, tests may be performed at any time; however, completion is required by the month stated as outlined in Table 2, and 3: PPB program milestones, metrics and assessment metrics.

Throughout the program there will be two types of testing, Safety and Regulatory Testing and CB Testing, detailed below.

Safety and Regulatory Testing:

The PPB system (both TA1 materials and TA2 platforms) must be characterized for a variety of performance metrics beyond protection against agent. All metrics are detailed in Tables 2 and 3.

A significant portion of this characterization should happen in concert with FDA guidance and will require a testing plan to be created by the proposing teams in concert with the IV&V partners. Performance assessments that do not involve CB agent protection are expected to occur in parallel with milestone tests and must increase in complexity and comprehensiveness with each subsequent Phase (see IV&V Testing and Evaluation (T&E) of PPB System). The execution of non-agent tests can utilize the IV&V test team facilities or be conducted independently by the performers with IV&V oversight. These assessments should provide an in-depth understanding of the mechanisms of protection, failure modes, host toxicity, on- and off-target activity within the host, host-immunity (or autoimmunity), host-toxicity, and other factors that will affect performance/safety of all components of the PPB system. Many of these factors will be TA specific and should involve preclinical models with and without protection, under both ‘on’ and ‘off’ conditions (chemical removal or inactivation of TA2 platform components).

Safety testing should demonstrate that preclinical models donned with TA1 and TA2 components (under all states; ‘on’, ‘off’) remain within pre-defined ‘normal physiologies’. The results and analysis accumulated throughout Safety and Regulatory Testing should be used to periodically update the FDA during pre-submission meetings, incorporating FDA feedback in any updates to the testing plan as it progresses. This entire dataset will then be used as part of the IND or other submissions prior to human testing in accordance with regulatory guidance.

Proposed safety testing must, at minimum, include:

Months 0–12: Acute responses (minutes to hours) o Proposers must define the kinetics of PPB mediated protection, PPB mediated toxicity, and establish a baseline for acute responses related to:

temporal requirements for, and magnitude of, PPB protection;

on/off capability, and associated toxicities (with on- and off-states) at the level of cell, tissue, and organ; (TA2) physiological responses raised by PPB platforms, including thermal stress and immune responses developed against PPB (i.e., immune cell activation, inflammatory response, and cytokine release);

standard toxicology studies; and molecular and histological analyses of tissues.

Months 12–24: Persistent responses (days to weeks) behavioral responses in preclinical models to include waking, sleeping, feeding, grooming, etc.;

delivery device development;

route of administration; and dosage.

Months 25–36: Chronic responses (months) and extensive longer-term safety characterization of PPB ensemble including:

toxicology;

reproductive toxicity;

shelf stability; and ease of delivery.

Proposers must assess, beyond survival/death, the impact of PPB platforms on all of the subcategories (acute, persistent, and chronic) and symptoms relevant to the specific threat(s) investigated. Specifically, performers should ensure that there is an absence of clinical symptoms post-exposure to CB agents for an observation period of 30 days. Proposers must also quantitatively define and describe a method to measure duration and magnitude of the TA2 PPB protective response in vivo, and demonstrate the removal of PPB TA2 platforms, i.e., clearance through excretion, host mediated clearance, or pharmacological means.

CB Agent Testing:

Proposers will develop PPB platforms to protect against CB threats listed in Table 1.

Development of platforms against select threats should remain consistent throughout the program, with the exception of Adaptation Tests. Performers may utilize surrogates for CB agents as systems are under development; however, all testing will be reviewed, approved, and monitored or conducted by IV&V partners. All live agent tests will be conducted by IV&V partners in a facility permitted to work with these agents and will use CB agents explicitly listed in (Table 1). As PPB platforms represent an entirely new approach to individual CB agent protection, new testing methodologies will need to be developed and will build on existing standards, such as the Test and Evaluation Capabilities and Methodologies Integrated Process Team (TECMIPT) test operations procedures TTOP08-2-109 and TTOP20141201-1. Finally, it is not within the scope of this program to propose research of chemical or biological agents not explicitly listed in Table 1.

Table 1 indicates the list of threats that are within the scope of the program. Within Table 1, all proposals should, at a minimum, demonstrate PPB functionality against either active, or simulant of specified threats as indicated. Proposers should develop platforms that can protect against all threats listed in Table 1.

Table 1 List of CB agents for TA1 & TA2

IV&V for Testing & Evaluation (T&E) of PPB System:

IV&V teams will support proposers as a Government-furnished service for all agent testing leading up to program milestones and will conduct all agent testing for evaluation against program metrics/milestones.

Simulant and Agent Testing: IV&V teams, with performer input, will design and provide a standardized testing plan for evaluation of PPB components exposed to CB agents at levels equal to or in excess of lethal doses (LD) or concentrations resulting in immediate danger to life or health (IDLH). Test designs will be submitted to DARPA six (6) months prior to agent challenges as indicated in Tables 2 and 3.

Analog tests (i.e., inactivated, simulant, or surrogate agents) will be designed and executed in collaboration with IV&V as a part of milestone/metric evaluations. As a part of this, proposers will collaboratively identify clinically relevant ex vivo and in vitro systems with the IV&V team, based on feedback from FDA interactions at the beginning of the program.

For each in vivo model challenge, IV&V teams will work with performers to identify clinically relevant small or large preclinical models. Selection of in vivo models will also consider relevance for the chosen CB threat type as it relates to human response and etiology (e.g., mode and magnitude of exposure, citation of literature supporting the model with physiological and molecular responses relevant to human exposure).

TA1-specific testing: Assessments that do not involve CB agent protection, such as wear, thermal, and breathability evaluations, are expected to occur in parallel with milestone tests and must increase in complexity and comprehensiveness with each subsequent Phase to meet the metrics in Tables 2 and 3 by the end of the program. The execution of non-agent tests can utilize either the IV&V test team facilities or be conducted independently by the performers with IV&V oversight, ensuring compliance with the IV&V-defined test plan.

1.4. PROGRAM SCHEDULE, MILESTONES & METRICS

Figure 2: PPB PROGRAM SCHEDULE

Phase I (Base Period)

During Phase I, proposers will develop platforms that prevent (TA1) and neutralize (TA2) broad spectrum CB threats from accessing the body at vulnerable tissues (i.e., ocular, respiratory, dermal).

Feasibility Study (6 months) – TA1 and TA2

Performers will conduct feasibility studies within 6 months of being on contract. Feasibility studies will demonstrate 1) active team-IV&V communication, 2) fundamental technical aim components (e.g., chemical reactive groups, organisms, nanomaterials), and that technologies 3) can function in a manner that is consistent with program goals. Data will allow IV&V teams and DARPA program management to provide guidance in the design process and experimental procedures. This feasibility study will also facilitate early establishment of important working-relationships (IV&V, teaming, FDA).

Test 1 (12 months) – TA1 & TA2: Material and Platform Development

Performers will demonstrate capability of protection with up to three (3) designs consisting of materials (TA1)/platforms (TA2) in ex vivo/in vitro models against relevant simulants as approved by IV&V. Further details are outlined in Table 2: PPB program milestones, metrics, and program assessment metrics Phase I.

Test 2 (18 months) – TA1 & TA2: Material and Platform development

Demonstrate in vivo protection against threats as listed in Table 1 and outlined in Table 2.TA2 platforms will be required to demonstrate responsiveness and functionality with simulants and active agents as approved by IV&V (Table 1), in preparation for Test 3.

Test 3 (24 months) – TA1 Material Performance (Testing to occur at IV&V facility)

By 24 months, TA1 designs will be required to pass thermal, mechanical, and environmental tests designed by IV&V teams to evaluate compatibility with both strenuous activity and outdoor conditions without agent present using material swatches or equivalent constructs. Details are outlined in Table 2. Environmental and functional tests will be conducted as technologies mature in Phase 1 and will continue into Phase II with fully developed, wearable constructs. This is not a program assessment component of the Test 3 event.

Test 3 (24 months) – TA1 & TA2 Material and Platform Protection (Testing to occur at IV&V facility)

TA1 and TA2 technologies will be functionally transitioned into in vivo models. IV&V teams will test at most three (3) individual materials and three (3) platforms per team (3, TA1 and 3, TA2) against one (1) performer selected chemical agent and one (1) performer selected biological agent, achieving 100% protection in vivo.

Protection tests will require administration/donning of candidate PPB platforms (where donning is possible; otherwise tests will be done via barrier testing), followed by an immediate (within 1 hour) threat challenge to an in vivo model. Over a 30-day monitoring period multiple CB agent exposures (lasting no more than 12 hours) will be conducted in order to validate the duration of protection. Each platform submitted for Protection Tests should meet defined metrics (Table 2).

Exposure routes for BCM Protection Tests will be performer selected but limited to vulnerable tissue barriers (i.e., ocular, respiratory, dermal). The outcome of candidate PPB platform Protection Tests should demonstrate (1) long-term, (2) broad-spectrum, and (3) durable protection capability, as defined in Table 2.

Test 4 (24 months) – TA2 Platform Adaptation & Protection

By 24 months, TA2 proposers will participate in a second in vivo test assessing the ability of BCM candidate platforms to adapt and provide 100% protection against a proposer-unknown, DARPA-specified agent at IV&V determined concentrations and durations. Assessment will be based on pre-defined metrics (Table 2) in IV&V assessment as well as all accessory data generated up to 24 months. Performers may submit up to three (3) individual BCM platforms for assessment. DARPA will announce a selected agent from Table 1 and IV&V teams will select appropriate preclinical models. Performers will have 21 days to ‘adapt’ BCM candidate platforms to protect against the ‘new threat’ and deliver BCM platforms to IV&V teams for challenge testing.

IV&V teams will select the vulnerable tissue barrier to challenge (i.e., ocular, respiratory, epithelial). IV&V teams will don/administer BCM platforms using in vivo models, where appropriate (noting the need for barrier tests where donning is not possible with certain models), and perform the challenge immediately (after 1 hour of donning). Sequential agent challenges (lasting less than 12 hours) will be administered over a 30 day period to ensure BCM mediated protection against novel threats, as well as safety, compatibility, and tolerability of BCM platforms. The outcome of candidate BCM platform Adaptation Tests will demonstrate (1) long-term effectiveness (30 days), (2) adaptability, and (3) durable protection capability (metrics in Table 2).

Regulatory process

During Phase I, proposers must actively engage the FDA/regulatory agencies, prior to drafting and submitting a Target Product Profile (See Tables 2 and 3). Active engagement may be informal or formal (e.g., FDA pre-pre-IND and/or EUA discussions) and will aid in the development of PPB, guidance in GMP manufacturing and fabrication, and clinical translation.

Rigorous safety testing throughout Phase I will be within FDA guidance, TPP submission, and IND or EUA application drafting.

Phase II (Option One)

During Phase II, proposers will focus on optimizing and expanding the capabilities of their PPB platforms. Up to three (3) platforms for each TA, per team, may move forward into Phase II to best integrate TA1 and TA2 into a PPB ensemble.

Safety, efficacy, specificity, and transience of the integrated PPB ensemble must be tested in vivo during every test. A series of sequential tests of increasing difficulty will be designed to assess the ability of the PPB ensemble to protect against selected threats prophylactically (pre-exposure) in healthy threat-relevant preclinical models. Tests will demonstrate greater in vivo protection and a greater understanding of the mechanism of PPB protection and failure.

Feasibility Study (30 months) – TA1 and TA2 Ensemble

Performers will conduct an early Phase II feasibility study, in collaboration with IV&V partners, to demonstrate TA1 and TA2 integration efforts produce a PPB ensemble capable of functioning in a manner consistent with program goals. This study will enable performers to test and guide their technical designs. Data will allow IV&V and DARPA program management to provide feedback for the design process.

Test 5 (36 months) – TA1 & TA2 PPB Ensemble Safety

Proposers will continue to improve on technology metrics while scaling up CB agent protection and material performance on TA1 and TA2. Safety and toxicity tests (such as those outlined in Safety and Regulatory Testing) will be the focus of months 25-36. Proposers will outline (with guidance and testing support from IV&V) specific assays.

Test 6 (48 months) -- TA1 & TA2 PPB Ensemble Protection

By 48 months after contract award, proposers will demonstrate integrated PPB ensemble protection (100% survival) with appropriate preclinical in vivo models challenged against two DARPA-selected CB agents and DARPA-selected exposure routes, at threat-relevant agent concentrations determined by IV&V. Selected CB agents will not be announced to performers.

One PPB ensemble per team may be submitted for the PPB Ensemble Protection Test in the surety environment provided by IV&V teams. PPB Ensemble Protection Test will run a minimum of 30 days with exposures lasting up to 12 hours during the 30-day period. IV&V teams will equip preclinical models and/or robotic humanoid manikins with the PPB ensemble, challenge immediately (within hours) with both of the unannounced agent challenges (derived from the agent list in Table 1) periodically over the 30-day period. The outcome of candidate PPB platform Protection Tests will demonstrate (1) long-term, (2) broad-spectrum, and (3) durable protection against unannounced threats with zero adverse health effects from even low-level agent exposures to meet metrics in Table 3.

By the end of Phase II, the PPB ensemble should be capable of protecting a human, with regulatory (FDA) approval for in-human testing in Phase III of the program. Individually, TA1 solutions should be wear and weather resistant, pose near-zero thermal or logistical burden to the wearer, and protect against the pre-defined list of agents (Table 1) in accordance with metrics listed in Tables 2 and 3. TA2 solutions will be on-demand with hand-held delivery (e.g., eye-drops, inhalation, topical application, etc.).

Regulatory process

In the middle of Phase II (months 30-42), proposers will finalize all necessary IND/EUA application submission requirements, data analysis, platform optimization, and plans for technology transition. Proposers will demonstrate increased formulation versatility (shelf-stability, mass-producibility) and device delivery. At the end of Phase II, proposers will demonstrate the ability to develop PPB platform components in a GMP environment. Pre-EUA activities are not required but may proceed in parallel to the required FDA approval through IND pathways.

Safety testing of integrated PPB platform components such as those outlined in Safety and Regulatory Testing may be performed independently or coincide with IV&V tests. Rigorous safety testing throughout Phase II of the PPB ensemble will be within FDA guidance, in conjunction with robust on-going regulatory (i.e., FDA) engagement.

Phase III (Option Two)

In-human safety testing of PPB

The primary objective at the end of Phase III will be to translate the integrated PPB ensemble into human subjects for safety testing. The program will conclude with clinical in-human or on-human (as appropriate) safety study completion and transition of technology(ies). The end-objective for Phase III will be EUA granted from the FDA following a successful human study.

Milestones & Metrics

In order for the government to evaluate the effectiveness of proposed PPB technologies in achieving the stated program objectives, proposers should note that the government hereby promulgates the following program metrics that may serve as the basis for determining whether satisfactory progress is being made to warrant continued funding of the program. Although the following program metrics are specified, proposers should note that the government has identified these goals with the intention of bounding the scope of effort, while affording the maximum flexibility, creativity, and innovation in proposing solutions to the stated problem.

Quantitative metrics are expected to vary for each proposer-selected threat area and system.

Some exemplary milestones and metrics are included below for proposers to consider, but proposers should adjust accordingly for their given threat and system. Final metrics are to be determined at the time of award negotiation and are subject to DARPA approval. Proposers should note that program metrics may serve as the basis for determining whether satisfactory progress is being made to warrant continued funding of the program (i.e., assessment).

In addition to the tests and system demonstration milestones, performers will be required to participate in program review meetings every 6 months. All performers will attend these Technical Interchange Meetings (TIMs) to brief their latest results and progress toward program goals. The meetings will include government participation from FDA, Defense Threat Reduction Agency (DTRA), program agents, defense laboratories, and the potential customers including United States Special Operations Command (USSOCOM), U.S. Army Combat Capabilities Development Command Chemical Biological Center (CCDC CBC), U.S. Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD), and other interagency end-users. Government sidebars will be held to provide individual feedback to the performers and to ensure they are developing relevant technologies. Teleconferences will be held with each team at monthly intervals. Site visits will be conducted at the Program Manager’s discretion. Tables 2 and 3 are a summary of the milestones and metrics for each team throughout the PPB program.

Table 2: PPB program milestones, metrics and Phase I assessment metrics Phase I

Milestone IV&V Metric months

TA1 & TA2

Demonstrate feasibility

Platform Feasibility Study months

TA1

Determine material protection factor and break through properties in consultation with IV&V teams

Demonstrate protection against 5 CB agents or simulants

Provide data describing acute responses (minutes to hours) as outlined in Safety and Regulatory Testing)

TA2

Demonstrate neutralization of 2 CB agents or simulants Provide data describing acute cute responses (minutes to hours) as outlined in Safety and Regulatory Testing)

Test 1:

Material and Platform Development

(TA1&TA2)

months

TA1

Translate platform from ex vivo to in vivo Test plan developed in collaboration with IV&V, submitted to DARPA in preparation for Test 3

TA2

Translate platform from in vitro to in vivo In vivo on/off capability demonstrated within one hour Test plan developed in collaboration with IV&V, submitted to DARPA in preparation for Test 3 and Test 4

Test 2:

Material and Platform Development

(TA1&TA2)

TA1

Near instantaneous (within 10 minutes) protection Meet pre-determined acceptable protection factor and/or breakthrough properties (as determined in consultation with the IV&V teams) against 5 CB threats or simulants

TA2

Active within 10 minutes Neutralizes 2 CB agents or simulants Safeguard activated, gene expression shut off, or removal of platform (i.e. on/off control) demonstrated within 1 hour months

TA1

Safety studies to ensure host compatibility for TA1 technologies as appropriate. Performers must include inflammatory profiles preclinical models. Safety studies should run a minimum of the duration of protection (at least 30 days), and include the characterization while donned with PPB TA1 technologies

Persistent responses (days to weeks);

Test 3:

Material Performance

(TA1)

Test 3:

Material and Platform Protection

(TA1 &

TA2)

TA1 and TA2 Assessment metrics: 100% survival of preclinical models for at least 30 days against a lethal dose of 1 proposer-selected chemical, and 1 proposer-selected biological agent at IV&V defined exposure levels

Table 3: PPB program milestones, metrics, and Phase II & Phase III assessment metrics such as those outlined in Safety and Regulatory Testing

TA2

Safety and toxicity studies to ensure host compatibility for TA2 technologies as appropriate.

Performers must include characterization of toxicity and inflammatory profiles in preclinical models. Safety studies should run a minimum of the duration of protection (at least 30 days), and include the characterization of host under activation and deactivation of PPB platform components

Persistent responses (days to weeks);

such as those outlined in Safety and Regulatory Testing

Regulatory TPP submission to DARPA months

TA1

Demonstrate material technologies result in:

Near-zero burden Weather and wear resistance

TA2

Demonstrate BCM platform can be delivered on-demand by hand-held delivery device (e.g., eye-dropper, inhaler)

Regulatory Active engagement with FDA, and follow FDA guidance for IND/EUA application (minimum 2 meetings)

Test 4:

Platform Adaptation & Protection

(TA2)

TA1

Core body temperature does not elevate above 100.4°F Thermal insulation values are <0.7 clo Permeability (index 0.20-0.25) Logistical weight < 1.0 lb.

Hydrostatic resistance and breathability in excess of ACU performance Impact abrasion, seam burst strength, impact cut resistance exceed EN 13595:2002 protection and integrity standards (EN 13595-1 through EN 13595-4)

Reduced attachment of agent (4-orders of magnitude, relative to ACU)

TA2

Assessment metrics: Demonstrate BCM platform adaptation to a new biological or chemical threat within 21 days, providing comparable protection (100% protection, at least 30 days) in appropriate preclinical models model(s)

Phase II Milestone IV&V Metric months

Integrated TA1 and TA2 Platform components (TA1 & TA2) integrated into one PPB ensemble and compatible with appropriate large preclinical model(s)

Test plan developed in collaboration with IV&V, submitted to DARPA in preparation for Test 5

Feasibility Study

(TA1 & TA2

Ensemble)

TA1

Near instantaneous (within 10 minutes) protection Protection against 10 CB threats

(survival at IV&V-specified agent exposure levels) under conditions ranging from -20-+45 C, 0-100% RH, and up to 60 kts wind speed

TA2

Active within 10 minutes Neutralizes 5 CB agents Safeguard activated, gene expression shut off, or removal of platform (i.e. on/off control) demonstrated within 1 hour months

Integrated TA1 and TA2 Proposers will continue to perform specific assessment and reiteratively innovate PPB ensemble technologies in large preclinical models for weather resistance, wear resistance, and reduced burden (thermal, logistical) metrics

Safety and toxicity parameters (such as CBC, chemistries, cardiac, renal, and hepatic function) will be defined by appropriate large preclinical models, ensuring models are donned with the PPB ensemble remain within pre-defined ‘normal physiologies’

Chronic responses (months); such as those outlined in Safety and Regulatory Testing

Test plan developed in collaboration with IV&V, submitted to DARPA in preparation for Test 6

Regulatory (complete by 42 months) Finalize all necessary IND/EUA application submission requirements, data analysis, platform optimization, and plans for technology transition

Test 5: PPB Ensemble Safety

Integrated Ensemble Assessment metrics: Demonstrate

PPB ensemble compatibility, safety, and zero toxicity for at least 30 days in large preclinical models

Phase II Milestone IV&V Metric months Demonstrate ability to produce BCM

(TA2 component) in a GMP environment

Regulatory Assess, beyond survival/death, the impact of PPB platforms on all of the subcategories (acute, persistent, chronic) of potential impacts on the user of the PPB system to include autoimmune, adverse user experience, or other qualitative impacts

Test 6: PPB Ensemble Protection

Integrated Ensemble Assessment metrics: PPB provides 100% protection of preclinical models for at least 30 days when challenged with a lethal dose of CB agent

Phase III Milestone IV&V Metric months

Integrated Ensemble, in-human Penetration testing using TECMIPT or similar DUSA T&E environments for aerosol and vapor break-through testing

Regulatory Submission of PPB platform for FDA regulatory approval to support EUA and fielding of system through commercial or military acquisition systems

Provide human and/or manikin model testing environment, as necessary

Integrated Ensemble Zero adverse effects by human subjects Zero breakthrough of aerosol or vapor in human or manikin testing

Don/Doff <10minutes

1.5. GENERAL REQUIREMENTS

Controlled Unclassified Information (CUI) Statement To prevent the release of sensitive technical information, certain aspects of the proposed research may be considered CUI if they reveal host susceptibilities to threats or other vulnerabilities, and may require safeguarding or dissemination controls, pursuant to and consistent with applicable law, regulations, and government-wide policies. Proposals that anticipate the production of any such information must deliver a detailed risk mitigation plan to DARPA (see Section 4.2.2.

Proposal Format Section II: I). Performers must partition potentially sensitive tasks from nonsensitive research efforts. All performers (prime contractor and subcontractor) desiring public release of project information that may contain CUI as defined above must submit a request for public release from DARPA in accordance with their contractual requirements.

The PPB program will involve the development of PPE material technologies (TA1), which falls under Export Administration Regulations (EARs), and the research related to it will be treated as CUI for this program. The program will only investigate known threats (Table 1). TA2 developed technologies will have the potential to be rapidly reconfigured in order to mitigate or eliminate risks posed by novel CB agents. Details for TA2 platform reconfiguration will be considered CUI. Additionally, TA2 platforms will involve safeguards, with the potential for controlling activation and deactivation of TA2 provided protection. Safeguard controls, such as pharmacological sensitivity or induction/repression of protection, will be considered CUI.

To prevent the release of sensitive technical information, certain aspects of the PPB program may be considered CUI and may require safeguarding or dissemination controls, pursuant to and consistent with applicable law,…