Challenges to producing novel therapies – dried plasma for use in trauma and critical care

Challenges to modern dried plasma development exist at multiple points along the product development cycle and include the regulatory pathway, funding, logistics, implementation, and commercial viability. The regulatory path for these products requires a clinical development pathway similar to a drug that entails longer timelines and substantial funding. US efforts to develop a dried plasma product have been military driven in response to a demand arising from the Operation Iraqi Freedom and Operation Enduring Freedom conflicts. A memorandum of understanding has existed between the Department of Defense (DoD) and the Food and Drug Administration (FDA) since 1974 for the purpose of expediting review of special DoD requirements to meet national defense considerations and set the requirement for clinical testing through submission of an investigational new drug (IND) or investigational device exemption (IDE) application.1 Modern development of a US-based dried plasma product has been under way since the early 2000s, challenging expectations for an expeditious process. A new initiative between the DoD and FDA was announced in January 2018, with the goal of streamlining the product development path. This initiative, coupled with continued clinical investigation, will result in US dried plasma products being available on the market soon, and may demonstrate that these efforts have the potential to hasten future product development pathways. Demand for freeze-dried plasma (FDP) production arose from military need for a resuscitation fluid to treat hemorrhagic shock due to blood loss resulting from battlefield injuries.2 Widespread use of dried plasma began in the 1940s by US and British military forces during World War II for the primary indication of management of shock.2 Due to the large quantities of plasma needed, freeze-dried (lyophilized) plasma was produced by several biologic manufacturers by pooling thousands of units that were dispensed into glass bottles, freeze dried, stoppered upon completion of drying, and then packaged in tin cans to resist breakage. Location of the manufacturers was selected based on proximity to plasma collection centers to streamline production.2 The French similarly began manufacture of FDP to support military use during the Indochine War.3 US production efforts were eventually discontinued due to contamination of the large plasma pools with hepatitis B virus (HBV), with reported rates of transmission of hepatitis B virus during the Korean War of up to 21%.4 Pooled lyophilized plasma was formally withdrawn from use by the FDA in 1968 because of known risk of pathogen transmission.5 Concerns regarding transmission of human immunodeficiency virus suspended further development efforts in the 1980s. Production was reinitiated by the French in the early 1990s during the Gulf War to support military operations.3 The German Red Cross Blood Service West also began manufacturing in the 1990s a lyophilized pooled product that used the solvent/detergent method to remove pathogens.6 Since 1994, South Africa has manufactured a licensed, freeze-dried product, Bioplasma FDP, made from pools of solvent detergent–treated plasma to yield a pathogen-reduced, ABO-compatible product, based on Octapharma's solvent/detergent product.7, 8 With the start of Operation Iraqi Freedom, a body of research emerged supporting the early use of plasma and at a 1:1:1 plasma, platelet, red blood cell (RBC) ratio for improved survival outcomes.9-12 In 2007 and 2008, the US Army Medical Materiel Development Activity (USAMMDA) and US Army Special Operations Command began funding development of dried plasma programs with initial awards to HemCon Medical Technologies for the development of single-donor lyophilized plasma in a ruggedized container. In 2008, the Office of Naval Research funded development of a pooled, solvent/detergent, universal, spray-dried plasma product (Resusix) with Entegrion Inc. In 2012, the Biomedical Advanced Research and Development Authority (BARDA) funded development of another spray-dried technology with Velico Medical Technologies that has a decentralized manufacturing model for a single-donor product called FrontlineODP (OnDemandPlasma). In 2013, Vascular Solutions, a subsidiary of Teleflex corporation, continued the freeze-dried development program for single-donor lyophilized plasma (RePlas) with support from USAMMDA. Terumo BCT received military funding in 2016 to develop a decentralized, freeze-dried plasma manufacturing capability for use at blood centers. The advent of emerging pathogen reduction technologies to mitigate transfusion-transmitted diseases highlights the potential synergy for a long storage shelf-life product like FDP, representing the next incremental step in the development of a dried plasma product. Two companies with pathogen reduction technologies are Cerus Corporation, with the Intercept technology that uses amotosalen activated by ultraviolet A, and Terumo BCT, with Mirasol technology combines riboflavin with ultraviolet B excitation to inactivate pathogens. The licensed French product French lyophilized plasma (FLyP) is manufactured from small pools (<11 donors) of leukoreduced fresh frozen plasma (FFP) that is pathogen reduced with Intercept treatment.3 Due to risk of transmission of Creutzfeldt-Jakob disease, the German Red Cross Blood Service West switched to their current licensed product LyoPlas N-w, made from single-donor tested and quarantined FFP units.6 Both French and German dried plasma products were used in Operation Iraqi Freedom and Operation Enduring Freedom with published reports supporting its use in the prehospital setting, and both are licensed for use outside of the United States.3, 6, 13-15 With the long lead time for FDA approval of a US-based FDP product, the US military, through White House discussions, received FDA approval to partner with the French Centre de Transfusion Sanguine des Armées and utilize the French product. US military operations has had limited use of the FLyP product that is manufactured using donor retested (quarantined) plasma, without the pathogen reduction step, through an expanded-access IND since 2011.16 In July 2018, FLyP received FDA clearance through an emergency use authorization permitting military operations use for treatment of hemorrhage or coagulopathy when FFP is not available or practical.17 Unlike FFP, which was "grandfathered in" as a licensed product, current dried plasma products are required to follow a regulatory path that is predicated on drug development and handled through the blood products division at the Center for Blood Products Evaluation and Research (CBER). This development path entails comprehensive in vitro characterization and can require in vivo pharmacology/toxicology studies for filing an IND application or IDE application. Additionally, most US dried plasma products currently under development have accompanying disposables that may be qualified under the IND/biologics license application pathway, or may be viewed as a separate device requiring an additional 510(k) or IDE/premarket approval pathway. The regulatory pathway for US dried plasma products is more complex than for products manufactured in the European Union. Manufacture and use of lyophilized plasma has been possible in Germany and France partly due to regulatory approvals based on in vitro characterization, without a requirement for clinical trials. Additionally, both the German and French products are manufactured using traditional practices of freeze drying in stoppered glass bottles. US-based dried plasma products to date have progressed as far as completion of Phase 1 clinical trials evaluating safety of dose escalation in normal, healthy volunteers. HemCon and Entegrion completed Phase 1 clinical investigations,8, 18 and Vascular Solutions is currently completing a Phase 1 clinical trial (NCT02930226). It has been nearly 20 years since the DoD renewed efforts to develop dried plasma, and the estimated date for a product to market is 2019–2020. There is lack of consensus on required Phase 2 and Phase 3 trials to gain approval for the indications of FFP without having to conduct a separate clinical trial for each of the indications listed in the AABB Circular of Information. Trials such as the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMTT) study and the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) trial demonstrate the feasibility of conducting trauma trials, which clearly have relevance to military and prehospital settings. However, there remain the challenges of nonhomogeneity of trauma patients and their injuries, defining the most clinically relevant outcomes and time points such as mortality at 6 hours, 24 hours, or 30 days, as well as gaining exception for informed consent. The following table lists registered clinical trials investigating the use of plasma. The first three studies involve the use of German and French lyophilized plasma in trauma and prehospital settings. Three US-based dried plasma products have undergone Phase 1 investigations in healthy volunteers. The last three studies are US-based investigations of prehospital use of thawed plasma (Table 1). There are distinct decision points in the development of a manufacturing capability. Centralized manufacturing facilities can follow the proven manufacturing model using clean rooms to transfer plasma into the plasma container. Manufacture outside of a clean room space, as would be required in a decentralized manufacturing model, necessitates development of a closed system that can be utilized in a blood center facility or non–clean room environment, without major changes to the existing facilities. This poses increased regulatory challenge of development of a manufacturing process and "functionally closed" disposable that can ensure aseptic processing and the absence of unwanted infectious agents. Blood products, like cells, have biologically active components that cannot be subjected to terminal sterilization.19 Manufacture of dried plasma using glass containers and rubber stoppers was successfully implemented in WWII. Both the German and French products are manufactured using stoppering techniques and glass bottles that are well characterized and routinely used in the pharmaceutical industry. While this approach eases the regulatory burden, it does not meet the military customer requirement.8 Single-use, nonglass, disposable, sterile containers that hold dried plasma have multifaceted roles. They serve as receptacles for the thawed plasma and are integral to the manufacturing process, withstanding exposure to a range of temperatures, pressures, and flow of gases or liquids. In addition to housing manufactured product, the container may serve as the final packaging for long-term storage, transport, rehydration of the final transfusable product and be compatible with blood administration set for direct transfusion to the patient. Packaging also has to demonstrate container integrity over a 1- to 2-year shelf life in a range of environmental conditions. These requirements have increased the regulatory burden of developing novel plastic containers. Container closures are difficult to validate and require substantial data to show container closure integrity. US military clinical experience with FDP was made possible by a regulatory mechanism called an expanded-access IND that allowed limited military emergency use since 2011. Length of the projected timelines for the clinical development path coupled with increasing evidence of benefit with early and aggressive administration of plasma for damage control resuscitation led the USAMMDA and the US Army Special Operations Command to seek the option of using an expanded-access IND in order to make dried plasma available for military use.20 While FFP or thawed plasma is available for use, it is logistically inferior to dried plasma due to the required cold chain management from the point of manufacture to the point of use. Until recently, French-manufactured FDP has been available for the US military through this expanded-access IND and distributed and managed by the USAMMDA's Force Health Protection Division. In July 2018, the FDA issued an Emergency Use Authorization under the Federal Food, Drug and Cosmetic Act, at the request of the DoD, authorizing the emergency use of FLyP in all military operations when FFP is not available or practical, reducing the required regulatory documentation needed for each product transfused.17 A joint pilot program between the DoD and the FDA was launched in January 2018 to prioritize medical product development, with the goal of expediting development and availability of safe and effective medical products to support battlefield medicine and for provision of the best care for soldiers.21 This effort has the support of the Assistant Secretary of Defense, Tom McCaffery, and the FDA commissioner, Dr. Scott Gottlieb. As an update to the last modification of the memorandum of understanding in 1987, this represents an advancement of the DoD's and FDA's approach to addressing regulatory challenges that accompany product development. Blood centers in the United States are rapidly moving away from manufacturing the traditional "gold standard" FFP product that is manufactured and frozen within 8 hours, and moving to production of a plasma frozen within 24 hours (PF24 and PF24RT) because of increased flexibility for blood center mobile collection operations.22 While PF24 is being used interchangeably with FFP, it has slightly lower levels of labile factors such as factors V and VIII and protein C.23 For emergency, prehospital use, universal type AB is required to eliminate need for blood typing. Prioritization of AB plasma is for Level 1 trauma centers and the military for emergency use, further limiting availability. Low-titer type A plasma can be used in lieu of AB plasma, but AB is preferred to reduce the risk of transfusion-related reactions. The military has been using low-titer A plasma under clinical practice guidelines due to the limited availability of AB plasma in the US population. Dried products produced in a centralized manufacturing model will require distribution of product to the customers. The military has well-established acquisition and distribution channels managed by the Armed Service Blood Program, though the current distribution of FLyP is being managed by the USAMMDA Force Health Protection Division.16 Civilian product distribution will require either working with blood centers that have well-established distribution channels, or selling directly to hospitals, group purchasing organizations, and emergency medical services. Velico's and Terumo BCT's approach is a decentralized model in which the blood centers purchase the manufacturing equipment and disposables and manufacture the dried product under an amended biologics license application, enabling blood centers to manufacture, sell, and distribute the dried plasma product. Reports of military and civilian use of prehospital plasma has spurred funding for conduct of US-based, prospective, randomized clinical trials investigating use of prehospital plasma for treatment of hemorrhagic shock to demonstrate safety and efficacy.24, 25 The premise of prehospital use requires plasma transfusion before or during air medical transport prior to arrival at a hospital emergency department (ED), and this was not part of the standard of care at the participating trauma sites in the PreHospital Air Medical Plasma (PAMPer) study.26 Only recently have air medical evacuations begun to integrate use of blood products in the United States that requires development of transfusion protocols, staff training, and auditable documentation.27 Blood products in the US are physician prescribed, which creates a logistical issue, as this differs from how prehospital blood products would ideally be administered. In the US, prehospital use of blood products entails the use of physician extenders or remote communication with physicians to approve the administration of blood products. Most EU countries have physicians as part of the air and ground emergency transport teams, yet this is not standard practice in the United States. Methods developed by military trauma systems in Afghanistan also support practices that encourage early use plasma as part of a prehospital damage control resuscitation.28-32 These demonstration studies and military trauma registry reports are helping pave the way for changing how blood products are administered in a prehospital setting and are critical for enabling implementation of a dried plasma product. The DoD and BARDA have provided the majority of funding for development of dried plasma products. As with other medical products, securing adequate funding to avoid the valley of death that exists between the initial feasibility stage and the scale-up and commercialization phases through the initial product launch is critical until revenue can be recognized. Attracting investment is challenging because the market size is not well defined and anticipated profit margins are not as large as for typical biopharmaceuticals. Company business models require a clear understanding of the capital investment needed as well as realistic returns on investment (ROI). Government investment in development efforts is intended to incentivize positive ROIs for companies, but ultimately success of a dried plasma product is dependent on broad commercial adoption beyond government customers. Dried products require an accompanying solution for reconstitution, similar to dried pharmaceuticals in vials. The main requirement is that the product be easily and rapidly rehydrated. Reconstitution solutions consist of sterile water for injection and may contain an additive to serve as a stabilizer or for pH adjustment. An off-the-shelf standard product available in 250-mL or 500-mL bag volumes is the easiest option. However, if nonstandard volumes or addition of additives are desired, then a custom fill is required. There are a limited number of companies that will manufacture custom fills for parenteral fluid volumes and even fewer that will manufacture the relatively small quantities required for early phase clinical trials because of the work required to perform validations for custom fills. Design considerations should also include connection ports that are unique so that reconstitution fluid won't be mistaken for an intravenous fluid. Packaging the reconstitution fluid with the dried plasma as a kit is an option, though kitting can be problematic over duration of shelf life since the dried plasma is hygroscopic and will readily absorb moisture. This problem is obviated by use of glass bottles. Beyond the FDA requirements for contamination prevention and ensuring an aseptic or sterile product for the duration of shelf life, requirements for packaging have been primarily defined by the military since they have the immediate need for use in prehospital settings and are driving development efforts. The primary military requirement is for a ruggedized, lightweight container that easily can be incorporated into an individualized first aid kit. Glass bottles are used for the French and German products due to the availability of well-characterized containers and processes that eliminate the need for significant development, thereby minimizing the regulatory burden. However, use of bottles does not meet the requirements set forth in the DoD program.8 Development efforts also need to incorporate requirements for the civilian market to produce a commercially viable product. For emergency, prehospital use, universal plasma is a key product attribute because it eliminates the need for blood typing prior to transfusion. While there is a low prevalence of type AB "universal" blood group in the population, low-titer A plasma can be used in lieu of AB plasma; however, AB is preferred to reduce the risk of transfusion-related reactions. Pooled products such as the FLyP and Entergrion's Resusix, offer a final product that is ABO compatible and considered universal and therefore can be administered without blood typing. One potential trade-off is that the large-scale pooling necessitates viral inactivation or pathogen reduction steps, and the additional manufacturing step has the potential to reduce the levels of clotting factors.33, 34 Dried plasma products made from single-donor plasma units are known to have wide variability in coagulation factor levels. Single-donor plasma units are the source of plasma products in the US, while EU countries have greater experience with pooled and pathogen-reduced products. Pooling provides uniformity of product and makes generating specifications and testing for product release more straightforward. Manufacturers of dried plasma made from single-donor units have to take unique approaches to testing for safety and potency, as most testing is destructive and it would be cost prohibitive to test every unit.19 Additionally, current plasma products such as FFP and PF24 are not tested for sterility or coagulation factor levels. The FDA has set a +/− 20% range for coagulation factor recovery as a measure of potency or demonstration of lack of change due to the manufacturing process. The challenge is characterizing the product for the specific manufacturing process and determining the most reliable and least burdensome measure for product quality and release testing. In addition to current practices that safeguard US blood products, pathogen reduction technologies can be incorporated into the manufacturing process to enhance product safety of dried plasma products. The combined manufacturing processes have the potential to reduce overall coagulation factor profiles, though FLyP and Resusix products demonstrate good factor retention.3, 34 Implementation of dried plasma products is being driven through several mechanisms. Development of a foundation of research based on preclinical investigations of dried plasma in models of polytrauma and hemorrhagic shock,35, 36 traumatic brain injury,37, 38 and models further elucidating the mechanism of endotheliopathy of trauma39, 40 support the use of plasma and dried plasma for trauma. The breadth of these investigations reflects an appreciation that the protective mode of action of plasma may be attributable to a broader effect of plasma as a balanced component for a range of abnormalities associated with trauma and shock.41 Hospital and prehospital studies using plasma, in addition to reports of use in military operations, are setting the stage for implementing dried plasma products for clinical use in the United States. There are multiple reports on the use of the FLyP and German LyoPlas N-w products overseas in support of military operations.3, 13, 14, 30 A civilian clinical study of FLyP for treatment of trauma in the ED reported improved fibrinogen concentrations and improved coagulation factors with use of FLyP compared to FFP.42 The French are currently conducting a trial of prehospital use of FLyP (PREHO-PLYP, NCT 02736812) in a prospective study of 140 subjects. The German LyoPlas product has also been tested in a registered trial for ED and prehospital use in Norway, demonstrating feasibility and potential safety and benefit.43 Use of FLyP by the US military has previously been supported through the expanded-access IND and now is approved for use under the emergency use authorization. Additional studies are being conducted in the United States to demonstrate the benefit of plasma for civilian trauma in EDs as well as prehospital use. The prospective PROPPR study demonstrated a correlation of improved outcomes in damage control resuscitation with early use of a 1:1:1 ratio of plasma, platelets, and RBCs.44 The recently published prospective PAMPer trial, using prehospital thawed plasma for patients at risk for hemorrhagic shock, showed safety and reduction in 30-day mortality.26 Continued investigations through randomized, controlled clinical trials both here and in the EU are helping to further develop a safety database and evidence of efficacy, as listed in Table 1. The larger challenge to implementation is the ability to manufacture and sustain commercially viable products. The DoD and BARDA have established funding mechanisms that have been instrumental in dried plasma product development and have demonstrated commitment to advancing products to Phase 3 and commercial readiness. Ultimately, the civilian market will have to supplement military demand to sustain commercial viability. Important lessons can be gained from the commercialization of an earlier solvent/detergent blood product, PLAS+SD, which was introduced in the United States in the mid-1990s. Selection of a sole US blood center distributor antagonized other blood centers and, coupled with a three times greater-than-expected pricing for comparable FFP and reports of adverse events, eventually terminated the product.45 Pricing for dried plasma products is predicated on several factors. The starting material, plasma, has historically been a lower-value by-product of whole blood compared to the higher-priced platelet and RBC components. New demand for plasma makes it a higher-proposition-value product with the potential to increase costs. Additionally, FFP, which has been the gold standard for plasma, will be harder to secure as it is being replaced rapidly by PF24 and PF24RT products. The cost of goods also includes the cost of packaging for the dried product. Products with novel containers have to factor in costs that will exceed that of traditional blood bags or products made in glass bottles. Finally, dried plasma requires additional manufacturing steps to yield a dried product, contributing to overall costs. Dried plasma is intended for emergency use by trauma physicians and emergency responders for administration in the ED, prehospital arena, or rural, critical-access hospitals for a patient requiring stabilization prior to transfer. As reported in the PROPPR study, most Level 1 trauma centers in the United States have access to thawed or liquid plasma in the ED, so a higher priced dried plasma product would compete with cheaper, comparable products. While EDs or prehospital may be the first entry point for dried plasma use, requirements for emergent administration of blood products arise in other areas such as the operating room and labor and delivery. Dried plasma offers advantages over FFP because it eliminates requirements for frozen storage, reducing cold chain logistics and enabling access in prehospital and rural environments, has longer shelf life, and is ready within minutes, facilitating early intervention and potentially reducing wastage. Hospitals, affiliated group purchasing organizations, and emergency medical services are the intended purchasers in the commercial market. For Level 1 trauma centers, the case must be made for the value-based reimbursement that would justify the additional cost for a dried plasma product. Working with Centers for Medicare and Medicaid Services and insurance exchanges will be necessary for establishing a level of reimbursement that will distinguish the product from FFP. If a higher reimbursement can be recognized, hospitals and other end users will be more inclined to incorporate the product. Making this case will require prospective clinical trials that establish the efficacy and safety of early delivery of plasma to generate a health economic rationale for the higher-priced product. Pricing will also be influenced by whether the product is classified as a blood product or a biologic and whether it is manufactured by the hospital pharmacy, supporting a higher reimbursement, or whether it will be considered a blood product and distributed by the hospital blood bank. The use of cell therapy as a tool for emergency trauma care for the immediate resuscitative phase to prevent downstream, secondary tissue injury and promote regenerative repair represents a shift in the current model for damage control.46, 47 Long-term benefits could be improved by incorporation of cell-based therapies that are proving to be potent mediators of inflammatory responses and cytokine storms.48 A challenge for cell therapies is heterogeneity of trauma injuries, therapeutic targets, and cell therapy products.46 There are multiple cell types to be investigated for their therapeutic potential. Products' mechanism of action will need to be sufficiently understood to identify appropriate biomarkers of clinical effect and/or to develop appropriate potency assays.19 Development of a commercially viable cell therapy product will require defining a cell type for a discrete therapeutic indication and target for action in a traumatic injury that can demonstrate the benefit of cell therapy in clinical settings. The DoD Trauma Registry, as part of the Joint Trauma System, has driven clinical data acquisition, allowing near real-time evidence-based improvement without a formal clinical trial.28, 30 This trauma system registry will be essential for collecting data on cell therapy recipients to augment clinical trial investigations. Considerations for delivery of cell-based therapies include formulation and packaging of the product to promote ease of logistics in cold chain management, transport, storage, and preparation. The FDA will continue to focus on safety as it pertains to sterility assurance and container closure integrity. For far forward military operations, an established cell product versus a cell preparation may be desirable, though it will depend on the timing and location of cell therapy administration. Cell preparations can be accomplished easily through the use of automated cell separation systems. Creation of a validated requirements document, similar to what the Army developed for dried plasma, is critical for guiding product development and minimizing the multifaceted impact new products would have on the existing infrastructure. Pricing and reimbursement will be based on the ability to demonstrate success of the indication treated and the poor outcome avoided. Developing a health economic model to show a decrease in long-term care costs as well as a decrease in disability and lost productivity could provide incentive to insurers, such as workers' compensation, to support use of cell-based therapies. The new DoD/FDA partnership represents an evolution in the approach to addressing regulatory hurdles that accompany product development and will likely have an impact on advancing development and deployment of cell-based products. Continued forums for sharing "state of the science" will provide the necessary engagement from the DoD to generate enthusiasm and support for funding opportunities to continue research and clinical investigations.47 Ms. Buckley is a consultant for Velico Medical, Inc. and a former employee of HemCon Medical Technologies, Inc. Col. (Ret) Gonzales is the former director of the US Army Blood Program and a former employee of Terumo BCT.