GFI-Item4-CPP_Development_Summary_Final.pdf

CPP Development Summary

Offerors should thoroughly read and assess the contents herein so that past DoD development experience can be leveraged, to the greatest extent possible, to expedite achievement of the program objective: an FDA-licensed CPP product meeting the specifications listed in Table 1 of the SOO. The following represents a comprehensive summary of the DoD CPP development thus far.

CPP is a frozen platelet product composed of γ-irradiated [2500 centi-gray (cGy)] leukocyte reduced apheresis platelets stored in plasma and anticoagulant citrate dextrose solution A for up to 57 hours. After apheresis, the platelets are concentrated and cryopreserved in approximately 6% DMSO at -80°C ± 15°C, stored at ≤ -65°C. As prepared, 1 unit of frozen CPP contains approximately 2.8 x 1011 to 4.5 x 1011 irradiated platelets and approximately 6% DMSO in a volume of > 20 mL to ≤ 35 mL. CPP may be stored frozen for up to 24 months prior to thawing for transfusion.

Prior to clinical administration, CPP is thawed and re-suspended with sterile 0.9% sodium chloride for injection, then held for 30 minutes prior to transfusion. The re-suspended product, CPP contains approximately 2.0 x 1011 to 3.6 x 1011 irradiated platelets in sterile 0.9% sodium chloride solution in a volume of > 45 mL to ≤ 60 mL and approximately 1250 mg to 2530 mg residual DMSO. After removal from the freezer, CPP units are stable at room temperature (20°C to 24°C) for up to 4 hours.

Non-clinical Studies:

In vitro studies, performed by USAMMDA’s past industry and academic partners demonstrate that compared to LSP, CPP is potentially more hemostatically active. Such a characteristic is defined by irreversible changes to platelet activation, microparticle release, loss of in vitro functions including a reduced response to agonists and hypotonic stress, decrease in shape change ability, increase in thrombin generation, and a conversion to a procoagulant phenotype (PS expression) and increased numbers of microparticles

The following in vitro test panels were used to characterize CPP:

pH22ºC, pO2 (mmHg) pCO2 (mmHg) total platelet count platelet recovery (%) morphology by light microscopy (points) P-selectin (% CD61 Events) PS expression (Annexin V) (%) PS expression, (Lactadherin) (%) platelet microparticles (% CD61 Events) total platelet microparticles platelet Aggregation (ADP + EPI) (%) platelet aggregation (collagen) (%) thromboelastography (MA, r-time, k, Angle, LY30) glucose concentration (mg/dL) lactate concentration (mg/dL) extent of shape change (%), swirl hypotonic shock response (%)

CPP Phenotype Characterization:

A two site, in vitro study was performed to characterize the in vitro phenotype of CPP by comparing CPP to apheresis platelets (held under standard blood banking conditions for 5 days) subject to simulated transfusion (with a transfusion pump) in vitro. The report was submitted to FDA with acceptance.

Potency Marker Assay:

Past effort also include the development of protocols for the validation of a Thrombin Generation Assay (TGA). The validation protocol and report has been finalized and submitted to FDA with acceptance. Additional work to generate the thrombin potency units, satellite sample comparison, and temperature degradation experiments are ongoing. To date, FDA correspondence has indicated that a validated TGA potency assay will be required before the start of the Phase 2 clinical trial. Additional discussions will be required to determine how to implement the TGA results. It has been suggested that they may best serve as a quality control measure during manufacture.

Based on prior FDA correspondence, the Government anticipates that the Offeror will need to utilize the validated TGA assay to evaluate the thrombin generating activity of CPP.

Additional methods of potency assessment may be viewed as favorable, particularly in light of the possible need to link in vitro potency to efficacy in clinical trials.

In addition, a protocol and report, “Lactadherin as a Negative Control for Thrombin Generation”, intended to assess degradation and specificity has been submitted to FDA with acceptance.

Manufacturing:

USAMMDA’s current Contract Manufacturing Organization (CMO) manufactured current Good Manufacturing Practice (cGMP) CPP lots for the Phase 1/2a dose escalation study using ISO-certified clean rooms. Recently, the CMO finalized a closed system to be used in an open space (without the need for ISO-certified clean rooms) for the manufacturing of CPP. This was evaluated using a 27% bagged DMSO and analyzing the vitro effects of platelets via a bridging study. The FDA accepted the closed system manufacturing after the successful completion of a media fill.

According to recent FDA correspondence, personnel performing manufacturing of CPP will be required to adhere to the same level of good laboratory practice as employees of the FDA-registered Blood Establishments to assure identity, strength, quality, and purity of the investigational product. Please note, however, that additional dialog will be necessary to clarify whether or not only FDA-registered Blood Establishments apply or if elements of the Biologic regulations will apply (i.e., a hybrid approach).

Shelf Life/Stability:

Stability testing was performed for CPP stored at ≤-65°C at multiple time points up to 24 months in accordance with ICH Stability Guidelines. Data was compared to historical CPP and single donor platelet (SDP) control data. Current CPP stability and shelf-life testing has shown a product shelf life of 2 years. Moving forward, the Government intends to explore increasing the stability to 5 years.

27% DMSO stability testing was conducted in communication/consultation with OriGen Biomedical. Note: OriGen Biomedical has submitted a Drug Master File (DMF#031830) for their DMSO in bags. The active IND #14047 references OriGen’s DMF.

Note: The Government anticipates that the Offeror will need to consider a formal audit of OriGen’s facility as a risk mitigation and due diligence activity.

Marking:

Efforts thus far have necessitated that each bag of CPP (IND or LRIP) comply with FDA approved product labeling, including the following markings:

International Council for Commonality in Blood Banking Automation (ICCBBA) approved label containing a Donor Identification Number that also includes the Facility Identification Number and the year manufactured or modified, blood type (ABO Rh), Expiration Date, Product Description (NB: Official description by ICCBBA) and the storage temperature.

For IND clinical studies a second label with the following statement: “Caution: New Drug - Limited by Federal (or United States) Law to Investigational Use.”

Note: Labels were affixed to the outside of the shipping container and on each individual bag.

Shipment and Storage:

Shipment and storage of the CPP product requires specialized cold chain management capable of maintaining temperature of ≤-65°C. This necessitates specialized shipping containers, temperature monitoring, and ultra-low freezers for long-term storage. The previous CMO validated a shipping container which is capable of holding 2 clinical units and maintaining a temperature of ≤-65°C during shipping. An additional shipping validation study (now complete) identified two (2) shipping containers capable of holding up to 4 units of CPP (during real life shipments) and maintaining temperatures of ≤-65°C.

At this time, the Government still needs to evaluate specialized freezers for military use of CPP. Accelerated fielding of CPP would likely be dependent on freezers already in the military system.

Training for product handling at combat support hospitals (Role 3), forward and resuscitative surgical team, blood support detachments (Role 2), or anywhere else that the product is envisioned to be delivered and used does not fall outside current skill sets of army blood bankers and technicians.

Clinical Development:

Multiple Phase 1 recovery and survival studies and a Phase1/2a dose escalation study (in actively bleeding thrombocytopenic cancer patients with WHO Grade ≥ 2 bleeding) were performed under a US Investigational New Drug (IND) application #14047. These studies demonstrated the in vivo viability of CPP, as required by FDA’s standards. In particular, the Phase 1/2A dose-escalation study indicated no thromboembolic complications from the transfusion of up to 3 units of CPP. Moreover, in no case did bleeding worsen despite patients being largely refractory to platelet transfusions.

USAMMDA has developed a plan and protocol for a Phase 2 adequately controlled learning efficacy trial in a bleeding patient population after undergoing complex cardiopulmonary bypass (CPB) surgery. The FDA has reviewed and approved the plan and protocol. In addition, USAMMDA has existing clinical site feasibility data and agreement from 10 CPB clinical sites (with corresponding blood centers) to participate in the Phase 2 clinical trial. At this time, the design and requirement for additional (Phase 3) clinical trials is to be determined and will likely be based on the outcome of the Phase 2 trial (see Note below). However, during preliminary discussions with FDA, a similar patient population (CPB surgery patient with post-surgical bleeding) was deemed acceptable. The FDA approved Phase 2 clinical protocol, IB, and ICF for the proposed Phase 2 clinical trial. The Government anticipates that the awardee(s) will conduct further correspondence with the FDA in order to generate a more complete investigational plan.

Note: As a result of the aforementioned FDA correspondence (RE: phase 2), the Government planned the following: At the completion of the Phase 2 study, a two stage analysis will be used to analyze the data. The results will first be tested with a 95% or higher confidence interval employed for testing non-inferiority. If the CPP versus LSP results are statistically significant for non-inferiority, the same 95% or higher confidence interval employed (for testing non-inferiority) with the pre-specified fixed margin will then be used to test superiority. This sequential testing will have the Type I error rates for both non-inferiority and superiority controlled at a level of no more than 5%. If superiority is shown, the data will be presented to the FDA for determination if it is sufficient to proceed for Biologic License Application or the necessary filing. If superiority is not shown, non-inferiority will be declared and a confirmatory Phase 3 trial in patients undergoing cardiopulmonary bypass surgery will be conducted.