BAA-NIAID-DAIT-NIHAI2015042_Attachment_5_Amended_2-4-16.pdf

ATTACHMENT 5: RESEARCH AND TECHNICAL OBJECTIVES

Development of Radiation/Nuclear Medical Countermeasures or Biodosimetry Biomarkers/Devices

NIAID-DAIT-NIHAI2015042

RESEARCH and TECHNICAL OBJECTIVES

The scope of this work to be funded under this BAA is the development of MCMs or biodosimetry biomarkers/devices.

Offerors are invited to submit proposals to advance the development of one lead candidate MCM or biodosimetry biomarker/device that has shown concept feasibility data. MCM drug candidates should increase survival by mitigating and/or treating acute or delayed radiation injury.

Biodosimetry biomarkers/devices should have the capacity to assess levels of radiation exposure and extent of tissue injuries from ionizing radiation.

Proposals should include a plan for conducting translational research and development and if applicable, provide additional information and data that support FDA approval or licensure and submission of an Investigational New Drug (IND) or Investigational Use Only (IUO) application.

Offerors should propose a well-defined product development path that includes IND/IUO-enabling studies that will be performed under the contract.

The goal of this BAA is to advance the development of safe and effective MCMs to mitigate or treat tissue injuries arising from exposure to ionizing radiation from a radiological or nuclear incident thereby leading to a reduction in radiation-associated morbidities and mortalities or the development and translation of biodosimetry biomarkers/devices for use in determining triage and treatment strategies of large populations. Specifically, this initiative is intended to support research and development of the most promising new approaches (including but not limited to:

biologics, drugs, cytokines, free radical scavengers, anti-inflammatory agents, antibiotics, cellular therapies, anti-fibrotics, and anti-apoptics) and medical products that measure, mitigate and/or treat radiation-induced tissue injuries.

The MCMs chosen for further development shall already have efficacy data (i.e., demonstrating clinically-relevant and statistically-significant reduction in mortality and/or major morbidity in appropriate animal models predictive of the human response) when administered/used at least 24 hours (or longer) after radiation exposure. The U. S. Government is looking to purchase and stockpile MCMs for civilian use that yield a significant medical benefit (reduction in morbidity and/or mortality) when administered at greater than 24 hours after radiation exposure, are suitable for a mass casualty incident (e.g., the preferred routes of administration are oral, subcutaneous, inhaled, transdermal or intramuscular), and are safe to use in normal, healthy individuals (in case appropriate biodosimetry is not available to confirm radiation dose received prior to initiating treatment).

The BAA supports development of biodosimetry biomarkers (biological indicators of radiation exposure such as intensity of radiation-induced tissue injuries), and other automated high-throughput diagnostic systems to rapidly assess levels and types of radiation exposure/devices using easily available biosamples. The biodosimetry biomarker/device chosen for further development shall already have data that demonstrates the capabilities of the biomarker/device to accurately and precisely measure absorbed radiation exposure levels to the body and/or tissues. A thorough understanding of how the biodosimetry will be used in a mass casualty incident within 72 hours (for triage) and beyond (for dose assessment and monitoring) should be demonstrated (e.g., time required for assay, process for testing accuracy of the biomarker/device and confounders such as: time from exposure, gender, age, health status, co-morbidities or illnesses). The intended stage of response of the biomarker/device shall be specified such as for preliminary triage purposes following a mass exposure event, or for medical management in a hospital setting at later post-exposure times.

Radiation exposure type, dose level, and dose rates proposed for studies need to be relevant to a terrorist incident or accidental exposure (e.g., nuclear power plant accident). Studies using fractionated radiation exposures, commonly used for clinical radiotherapy treatments would not be appropriate, unless information gained would be directly applicable to an unintentional exposure scenario.

It is anticipated that research and development studies awarded from this BAA will advance MCMs or biodosimetry biomarkers/devices toward submission of an IND application or IUO and eventual approval/clearance from the U.S. Food and Drug Administration (FDA) under the FDA Animal Rule (21 CFR 314.600-314.650, 601.90-601.95). Guidance for MCM approval has been provided by the FDA and is available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 399217.pdf.

Guidance for Radiation Biodosimetry Devices approval provided by the FDA is available at http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm427866.pdf.

This announcement is intended to support development activities for one lead candidate MCM or biodosimetry biomarker/device in any combination of the following areas (A. non-clinical R&D, B. manufacturing, and/or C. regulatory efforts):

A. Non-clinical Research and Development including:

For MCMs:

Animal model(s) development or refinement relevant to human radiation injury Reagent and assay development Efficacy studies in animals to optimize route of administration, formulation, dose, dose schedule, and dose reduction factor (DRF). Studies should be designed to be suitable (species, endpoints, measurements) for predicting future pivotal efficacy studies under the U.S. Food and Drug Administration (FDA) Animal Rule (21 CFR 314.600-314.650, 601.90-601.95). Efficacy is defined hereafter as a statistically significant improvement in survival in an in vivo model of radiation injury when the MCM is first administered 24 hours or later after radiation exposure

Mechanism of action studies relevant to human mechanism of action Bioavailability; pharmacokinetic; and adsorption, distribution, metabolism, and excretion studies GLP toxicology and pharmacology safety studies Formulation development, stability, and production scale-up

For Biodosimetry Biomarkers/Devices:

Development of biomarkers to rapidly assess acute and/or delayed radiation-induced injuries to physiological systems/organs/tissues to inform triage and treatment decisions, and/or assessment of injury and recovery of specific organ/organ system

Quantitative, and accurate means to distinguish between non-irradiated and exposed cohorts.

Studies should be designed in appropriate animal models, radiation quality, doses, and dose rate, and using easily available biosamples (e.g., minimum quantity of blood, hair follicles, skin swabs, saliva, serum, or urine rather than spinal fluid or tissue biopsy samples)

Reagent and assay development Mechanism of action studies relevant to human mechanism of action

Biomarker biokinetics (i.e., biomarker persists over a range of time permitting use in a radiation public health emergency – 30 minutes to days and weeks)

Influence of confounders on the kinetics of the technique/biomarker (e.g., gender, pediatric, geriatric population, smoking, health status, medications), different quality of radiation, partial body irradiation, other injuries (burn, trauma, wound).

Development of biodosimetry devices, high-throughput, or other automated diagnostic systems for rapid radiation dose assessment following exposure, research that supports quantification of the radiation dose to the exposed individual to inform treatment strategies, and/or assessment of injury and recovery of specific organ/organ systems.

Efficacy studies in appropriate animal models, using relevant exposure conditions (radiation quality, dose, dose rate), and using easily available biosamples to test the device.

IUO enabling studies for regulatory approval of advanced devices specific for the intended stage of response (triage or medical management), within a specified time-frame post-exposure (1-3 days post exposure for point-of-care, or 72 hours and beyond for medical management devices), and defined biodosimetry biomarker (e.g., RNA, DNA, multiparametric, metabolomics).

B. Manufacturing including:

For MCMs:

Formulation development, physicochemical and bioanalytical methods development Current Good Manufacturing Practice (cGMP) Manufacturing development and scale-up support Stability studies Manufacture of pilot lots of candidate product in amounts sufficient to carry out proposed non-clinical research

For Biodosimetry Biomarkers/Devices:

Pilot kits to test for stability, verification, and validation of the assay Development and optimization of biomarkers of radiation injury for preliminary triage purposes following a mass exposure event, or for medical management in a hospital setting at later post-exposure times

Performance testing to demonstrate robustness of the biomarker assay Pilot biodosimetry devices to test for stability, verification and validation of the assay Development and optimization of throughput capabilities, turnover time for the assay, as well as sample information (type of sample, volume, quantity, ease of accessibility) Performance testing to demonstrate robustness of device (for field triage) or for dose refinement to demonstrate measurement precision performance characteristics (for medical management)

C. Other IND/IUO or New Drug Application (NDA) and Biological License Application (BLA)

Activities including:

Development and drafting of GLP pivotal animal efficacy study protocols.

Development and drafting of Phase I human safety and pharmacokinetic study protocols.

Regulatory efforts to support pre-IND/IUO interactions with the FDA, drafting of an IND/IUO, and preparation of IND/IUO package.

Quality control over the implementation, coordination and conduct of the proposed activities.

Drug Master File (DMF) submissions under cGMP guidelines (see 21 CFR 314.420).

Organizations selected to receive an award as a result of this BAA will have identified a promising lead MCM candidate and have preliminary data demonstrating increased survival by mitigating or treating acute (ARS-Acute Radiation Syndrome) or delayed (DEARE-Delayed

Effects of Acute Radiation Exposure) injury in vivo in an appropriate animal model when first administered 24 hours or later after radiation exposure, or will have a promising biodosimetry biomarker/device demonstrating accurate radiation dose within ±0.5 Gy. The preliminary data will be included in a Target Product Profile, which will also include a description of the product, a summary of its intended use or indication, animal safety studies, a description of the manufacturing process and supporting assays, and any discussions with the FDA’s Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH) or Center for Biologics Evaluation and Research (CBER).

Offerors shall also provide their own Statement of Work (SOW), which describes the work that is proposed under the contract. Offerors shall also provide an Experimental Plan that provides detailed information on the specific product development activities that the Offeror is proposing to perform under contract funding. The Experimental Plan will include milestones and gates for Go/No Go decisions for advancing to the next stage of the Experimental Plan.

The following research activities are not within the scope of work for this BAA and the contract will not provide funds to support:

1. Screening activities to identify MCMs, biomarkers or devices.

2. Non-biologically-based dosimetric methods and/or environmental testing/sampling devices

(e.g. thermo-luminescent detectors (TLDs), fortuitous dosimeters, radiation portals, etc.).

3. Performance of clinical safety trials.

4. Performance of pivotal animal efficacy studies.