Cellular Therapy for the Treatment of Hemorrhagic Shock (CTTHS)

Purpose

This solicitation, issued by MTEC, represents a Request for Project Proposal (RPP) for MTEC’s support of the U.S. Army Medical Research and Materiel Command (USAMRMC) Combat Casualty Care technology objectives. Strategic oversight for the award(s) supported by this RPP will be provided by USAMRMC.

Trauma is the leading cause of death for individuals between the ages of one–44 and the third leading cause of death in the United States overall, accounting for approximately 180,000 fatalities each year, of which up to 20% are potentially preventable. Seventy-five percent of traumatic deaths occur during the first three days after injury and are primarily due to uncontrolled hemorrhage and traumatic brain injury (TBI). After three days, the remaining 25% of deaths accumulate at a low but steady rate and result from a complex interplay of inflammation, vascular compromise, and dysfunctional coagulation associated with the initial tissue injury, shock, and resuscitation. Clinical manifestations include acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), venous thromboembolism (VTE), Multiple Organ Failure (MOF), and cerebral edema and ongoing cellular death after TBI. Current treatments for these inflammatory conditions are supportive and efficacy trials for new interventions have all failed. Consistent and robust evidence supports the positive impact of rapid treatment for severe injuries including restoration of perfusion, oxygen delivery, and wound coverage; however, achieving rapid evacuation to damage control and definitive surgical treatment may prove impossible in future combat theaters. As a result, the military requires therapies that can mitigate the potential impacts of severe injuries and delays to surgical interventions in order to prevent mortality from combat wounds.

Pre-clinical, and some limited clinical, data support the hypothesis that cellular therapies may be of use in mitigating the sequelae of severe injury. Numerous studies have documented improved organ function, reduced secondary organ (e.g. lung, kidney) injuries, and improved survival with cellular therapy. In response to these and other findings of potential utility for cellular therapies, industry and academic institutions have developed prototype cellular therapy products that require further assessment in well-designed clinical studies to refine and advance the development of this prototype trauma therapeutics.

Therefore, MTEC is seeking to support a Phase II clinical study to evaluate the safety and efficacy of cellular therapy in the treatment of hemorrhagic shock in severely injured patients.

Later stage projects would be the most relevant to this request, such as those that are ready for human trials within 12 months. MTEC prefers that projects should be either entering formal U.S. Food and Drug Administration (FDA) supportive clinical trials or preparing documentation for upcoming regulatory submission to the FDA. This is not meant to support pilot lot manufacturing for animal study purposes. The proposal should include a clear description of the current status of the product.

It is expected that many of the actual cellular therapy projects may still be at the academic level, yet the manufacturing and clinical trial requirements demanded are most suited to industry. MTEC, therefore, considers that a teamed approach may have the greatest level of success, especially considering that the eventual goal is to transition products to industry for FDA approval.

Since this request is for technologies that are fairly advanced, it is anticipated that Government funds would provide incentive for industry funding to join the project. While not a requirement, Offerors are strongly encouraged to bring leveraged funding/cost share to complete the project goals.

Each MTEC research project proposal submitted must contain both a Technical and Cost Proposal Volume as described in Section 3 of this request, and must be in accordance with the mandatory format provided in the MTEC Proposed Performance Guidelinese (PPG) available on the MTEC website.

White papers are not required for this RPP. The Government reserves the right to award proposals received from this RPP on a follow-on Other Transaction Agreement (OTA) or other stand-alone OTAs as necessary to meet mission requirements.

Scope of Work

Technology Objectives

This call requests proposals for cell therapies that can be used to treat the inflammatory complications that arise after traumatic injury. (Note, this request is not looking for cell therapies that can be used to achieve hemostasis.) The intent of this action is to forward at least one cell therapy prototype into a Phase II clinical trial. Therefore, the products being brought forth must be ready to enter the clinical stage within a short window and have all of the regulatory requirements for IND prepared for submission as a minimum. The focus of this effort is the actual clinical study and not the manufacturing of product, albeit the product must be made available under GMP standards to move forward. If manufacturing is required, that must be stated and the cost identified accordingly.

MTEC seeks proposals from investigators comprising multi-disciplinary teams from a wide spectrum of disciplines including, but not limited to, engineering, translational research, and clinical research.

Proposed projects must be based on logical reasoning and sound scientific rationale. Please note that awards are not to be exploratory in nature and require a foundation of preliminary data.

Deliverables of the Proposed Work Should Include:

1. Produce clinical grade prototype cellular therapy agent in sufficient quantity to conduct a clinical assessment in a trauma patient population. Assessment needs to account for relevant regulations for prototypes to be administered to humans and ensure documentation of appropriate quality and process controls. The proposer will come forth with the appropriate protocol and surgical procedure that will serve as the basis for evaluation and supports labeling as a hemorrhagic shock therapeutic.
2. Develop a clinical study to assess mechanistic and outcome based patient responses to administration of cellular therapies with appropriate controls for administration of cellular therapy (placebo control, potential confounding treatments (e.g. inclusion/exclusion, hemostasis and blood transfusion) and outcomes assessment (blinding as to treatment)). Relevant outcomes may include inflammation and/inflammatory complications, organ function/injury scores, and mortality. In addition, all safety data and indications need to be identified for capture and review.
3. Document sufficient patient population (number, severity, availability in the acute post injury phase, and ability to conduct exemption from informed consent) to ensure assessment of prototype cellular therapy is conducted in a timely manner.
4. Consider capacity for future assessment of cellular therapies from a variety of sources (e.g. industry, academic labs, and international partners) in a well-described clinical population as a reimbursable service.

The Offeror's plan should cover all necessary activities to complete clinical evaluation, including all responsibilities commensurate with regulatory sponsorship including (but not limited to) safety reporting, clinical monitoring, data management, regulatory writing and submissions, stability reporting, and the Data Safety Monitoring Board (DSMB).

Clinical Plans should provide adequate technical details of proposed clinical protocol design(s), key personnel, clinical facilities, proposed clinical procedures, supporting laboratory studies, and postcharacterization data analysis including but not limited to the following:

• Clinical Protocols - Describe the clinical protocol to be used to evaluate the proposed cellular therapy.
• Clinical Capabilities and Clinical Support Setting - Clinical Plans should describe capabilities including key regulatory personnel (for example, a senior Regulatory Affairs Advisor, Principal Investigator (PI), and Associate Investigator(s)).
• Data Management Plan - Describe the data management plan.
• Clinical Monitoring - Offerors should describe a risk-based approach to clinical monitoring to ensure the protocol(s) are conducted in accordance with the principles of ICH E6, FDA GCPs, and requisite portions of 21 CFR. Deliverables anticipated from the successful Awardee for this activity include a clinical monitoring plan(s), clinical monitoring visit reports for each study, and corrective action tracking/reports adequately demonstrating management and resolution of any observed protocol nonconformance. Additionally, the clinical Monitors are expected to conduct site-initiation visits (SIV), for-cause visits, and closeout visits. Clinical Plans also should include appropriate details of the relevant support staff qualifications, capabilities and outpatient facilities for the proposed clinical trial site(s), ancillary out-patient clinical support settings, and any relevant biomedical laboratories or related facilities.
• Sample Collection and Analysis - Offerors should describe any specific clinical- and post-characterization plans to collect, analyze, store, maintain, and otherwise exploit ex vivo clinical samples from the clinical studies.
• Data Safety Monitoring Board - Offerors should describe, in general, a proposed DSMB structure and time points at which the DSMB will meet to review trial data.

Points of Contact

For inquiries, please direct your correspondence to Biomedical Research Associate Chuck Hutti, Ph.D. at Chuck.Hutti@ati.org.