Challenges to producing novel therapies – dried plasma for use in trauma and critical care (2019)

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 such as and and prehospital use, is required to need for blood of plasma is for 1 trauma centers and the military for emergency use, further A plasma can be used in of plasma, is to the risk of The military has been using A plasma under clinical due to the limited availability of plasma in the US products produced in a manufacturing model will require of product to the The military has and managed by the Service Blood the current of FLyP is being managed by the USAMMDA Force Health Protection product will require with blood centers that have or to and emergency medical and Terumo approach is a decentralized model in which the blood centers the manufacturing and disposables and manufacture the dried product under an license blood centers to and the dried plasma product. of military and use of prehospital plasma has funding for conduct of clinical trials investigating use of prehospital plasma for treatment of hemorrhagic shock to demonstrate safety and The of prehospital use requires plasma transfusion or during medical to at a emergency and this was not of the of care at the trauma in the Medical Plasma have medical to use of blood products in the United States that requires development of transfusion and Blood products in the US are which a as this from prehospital blood products would be In the prehospital use of blood products entails the use of or with to the administration of blood have as of the and emergency this is not in the United by military trauma in also support practices that early use plasma as of a prehospital damage control These studies and military trauma reports are the way for blood products are in a prehospital and are for of a dried plasma product. The DoD and have the of funding for development of dried plasma As with medical products, funding to the of that between the initial feasibility and the and through the initial product is can be is challenging because the market is not well and are not as large as for require a understanding of the needed as well as on in development efforts is to for of a dried plasma product is on commercial products require an accompanying for similar to dried in The requirement is that the product be and rapidly of sterile for and may an to serve as a or for product available in or is the However, or addition of are then a is There are a limited of companies that will manufacture for fluid and that will manufacture the small quantities required for early clinical trials because of the required to for considerations also include that are that fluid be for an Packaging the fluid with the dried plasma as a is an can be over of shelf life since the dried plasma is and will This is by use of glass bottles. the FDA requirements for contamination and an aseptic or sterile product for the of shelf requirements for packaging have been by the military since have the need for use in prehospital and are development The primary military requirement is for a container that can be into an first bottles are used for the French and German products due to the availability of containers and that the need for development, the regulatory However, use of bottles does not meet the requirements set in the DoD Development efforts also need to requirements for the market to a product. prehospital use, plasma is a product because it the need for blood to While there is a of blood in the A plasma can be used in of is to the risk of Pooled products such as the FLyP and a final product that is compatible and and can be without blood potential is that the pooling necessitates or pathogen reduction and the additional manufacturing step has the potential to the levels of plasma products made from single-donor plasma units are known to have in plasma units are the of plasma products in the have experience with pooled and of product and and testing for product more of dried plasma made from single-donor units have to to testing for safety and as most testing is and it would be to Additionally, current plasma products such as FFP and PF24 are not tested for or The FDA has set a range for as a of or of lack of due to the manufacturing process. The challenge is the product for the manufacturing process and the most and for product and In addition to current practices that US blood products, pathogen reduction technologies can be into the manufacturing process to product safety of dried plasma The manufacturing have the potential to FLyP and products demonstrate of dried plasma products is being driven through several Development of a of research based on investigations of dried plasma in of and hemorrhagic and further the mechanism of of support the use of plasma and dried plasma for The of these investigations an that the of of plasma may be to a of plasma as a for a range of with trauma and and prehospital studies using plasma, in addition to reports of use in military are the for dried plasma products for clinical use in the United There are multiple reports on the use of the FLyP and German LyoPlas products in support of military 30 A clinical study of FLyP for treatment of trauma in the reported improved and improved with use of FLyP to The French are currently conducting a trial of prehospital use of FLyP in a study of The German LyoPlas product has also been tested in a registered trial for and prehospital use in feasibility and potential safety and Use of FLyP by the US military has been through the expanded-access IND and is for use under the emergency use studies are being in the United States to demonstrate the benefit of plasma for trauma in as well as prehospital use. The study a of improved outcomes in damage control resuscitation with early use of a 1:1:1 ratio of plasma, and The published using prehospital thawed plasma for patients at risk for hemorrhagic safety and reduction in investigations through clinical trials both and in the are to further develop a safety and evidence of as listed in The challenge to is the to manufacture and The DoD and have funding that have been in dried plasma product development and have to products to Phase 3 and commercial the market will have to military demand to commercial viability. can be from the of an solvent/detergent blood product, which was in the United States in the of a US blood center blood centers coupled with a three for FFP and reports of eventually the for dried plasma products is predicated on several The plasma, has been a of blood to the and demand for plasma it a product with the potential to Additionally, FFP, which has been the for plasma, will be to as it is being rapidly by PF24 and The of also the of packaging for the dried product. Products with novel containers have to in that will that of traditional blood or products made in glass bottles. dried plasma requires additional manufacturing to yield a dried product, to plasma is for emergency use by trauma and emergency for administration in the prehospital or for a requiring to As reported in the most 1 trauma centers in the United States have to thawed or plasma in the a dried plasma product would with While or prehospital may be the first point for dried plasma use, requirements for administration of blood products in such as the room and and plasma over FFP because it requirements for frozen storage, reducing cold chain and in prehospital and has longer shelf and is within early and reducing and emergency medical are the in the commercial 1 trauma the be made for the that would the additional for a dried plasma product. with for and and will be for a of that will the product from a can be and will be more to the product. this will require clinical trials that the and safety of early of plasma to a for the product. will also be by the product is as a blood product or a biologic and it is manufactured by the supporting a or it will be a blood product and distributed by the blood The use of cell as a for emergency trauma care for the to and represents a in the current model for damage be improved by of that are to be of and A challenge for cell is of trauma injuries, and cell There are multiple cell to be for their mechanism of will need to be to of clinical to develop Development of a cell product will require defining a cell for a indication and for in a that can demonstrate the benefit of cell in clinical settings. The DoD Trauma as of the Trauma has driven clinical data without a clinical 30 This trauma system will be for data on cell to clinical trial for of include and packaging of the product to of in cold chain transport, storage, and The FDA will to on safety as it to and container closure integrity. far military an cell product a cell may be it will on the and of cell can be through the use of cell of a requirements similar to the Army for dried plasma, is for product development and the multifaceted new products would have on the existing and will be based on the to demonstrate of the indication and the a model to show a in long-term care as well as a in and to such as to support use of The new represents an in the approach to addressing regulatory that accompany product development and will have an on development and of for of the will the from the DoD to and support for funding to research and clinical is a for Velico Inc. and a of HemCon Medical Inc. is the of the US Army Blood and a of Terumo