By Mr. Jeffrey M Soares (Army Medicine)September 9, 2016
In the course of their service, the men and women of our military forces often need quick solutions to critical problems they encounter on the battlefield, and many of these answers come from the U.S. Army Medical Materiel Development Activity at Fort Detrick, Maryland. As a subordinate command of the U.S. Army Medical Research and Materiel Command, USAMMDA faithfully regards its mission to develop and deliver quality medical solutions to protect, treat, and sustain the health of Service Members worldwide. These solutions may come in the form of medical diagnostics, drugs or vaccines; however, in the case of an urgent request for the U.S. Army Special Operations Command at Fort Bragg, North Carolina, the answer was a blood product -- specifically, freeze-dried plasma manufactured by the French military -- and the USAMMDA teams came together to make this happen perhaps more quickly than ever before. In fact, they took only 23 days after their first meeting with USASOC to complete the extensive Investigational New Drug application for submission to the U.S. Food and Drug Administration.
Many would agree this truly represents a herculean effort.
To gain proper perspective on this, let's start with the backstory: In 2010, U.S. Navy Adm. William H. McRaven, then commander of the U.S. Special Operations Command, requested the U.S. Army Medical Command produce freeze-dried plasma that would be used to replace lost blood in severely injured Special Forces Soldiers in far-forward locations. McRaven had become aware that U.S. allied forces were using this product successfully in both Iraq and Afghanistan, primarily a French-produced FDP, and he wanted this to be made readily available for U.S. troops as quickly as possible. The primary obstacle, however, was that no U.S.-based FDP product had been approved for use by the FDA since shortly after World War II, due to the transmission of blood-borne pathogens. Regardless of this, the task had been issued, and an answer was needed.
With this call to action, the teams at USAMMDA -- namely, Force Health Protection, Division of Regulated Activities and Compliance, Clinical Services Support Division and Pharmaceutical Systems Project Management Office -- entered onto the scene to do what they do best: solving problems that help save lives.
"The DRAC team was brought in to support an IND for French FDP [manufactured by the Centre de Transfusion Sanguine des Armees]. However, based on our preliminary research on how it was being produced, we couldn't back it; we recommended using another sponsor, which ended up being a contractor in Florida," said DRAC director Dr. Robert Miller. "Unfortunately, the contractor worked on this for 18 months and made zero progress."
In response to this lack of headway, McRaven's team then arranged a White House summit meeting that included senior FDA officials and several USAMRMC personnel. Determined to move forward, McRaven's team soon gained the support of both groups, and an agreement was made to utilize the FHP and DRAC offices to secure an IND for French FDP, to use it as an interim solution while an FDA-approved U.S.-based FDP product could be developed.
"We were given only 30 days to write and file the IND paperwork [for French FDP], as well as to include the protocol for it," said Miller. "But keep in mind, in a real-world scenario, it typically takes three to six months to do all of this through the FDA -- and we only had 30 days."
In light of this -- and considering that Miller's DRAC team consisted of only six people -- completing all of the required documentation for submission in only 23 days is not only impressive, it's somewhat amazing.
"When my team heard that this was something the Army needed for our Soldiers, they pulled out all the stops and used a 'HESS' approach [Holidays, Evenings, Saturdays, Sundays] to get it done," said Miller.
"It's important to note that the FDA was extremely cooperative with us, and so were the people at USASOC, because the driving factor in all of this was to get the freeze-dried plasma to our Soldiers as quickly as possible," continued Miller. "If they needed it, there was no other option."
So why use a freeze-dried blood product anyway?
"Compared to fresh frozen plasma, the French freeze-dried plasma is a stable, dry product that can be kept at room temperature, in backpacks [in the field], and remains good for a long period of time," explained Dr. Kevin Spurgers, USSOCOM's contracted FHP product manager for the French FDP expanded-access IND. "It is reconstituted with sterile water when you're ready to use it."
The "expanded access" designation for this IND is what makes the FHP office essential to this effort, as its primary function is to manage expanded-access INDs, which are investigational products not being used in clinical trials.
"We have expanded-access protocols that allow us to use these investigational products in limited numbers of circumstances for U.S. Service Members in need, if they meet the inclusion criteria," said Spurgers. "We have these readily available in case they need it."
At this time, USSOCOM-procured French FDP is being used only by Special Operations Forces, and it is currently being deployed for USASOC Soldiers, with an annual stock of approximately 200 units. Spurgers' counterpart on the USASOC side is Maj. Rodney Saunders, who serves as the FDP clinical coordinator and study sub-investigator. Saunders performs a myriad of duties to ensure the successful deployment of French FDP to USASOC Special Forces Soldiers, and his responsibilities include the creation, revision and maintenance of regulatory files, program quality control, informed consent management and database administration for case report use.
When asked to describe the impact of FDP "on the ground," Saunders said, "Freeze-dried plasma fills a pre-hospital capability gap in damage control resuscitation. Early and aggressive use of plasma in pre-hospital [damage control resuscitation] is influencing both military and civilian trauma practice guidelines."
So, yes, FDP is a very important product.
"Special Operations Forces medical providers are at the tip of the spear, and have a product that bridges the gap between life-threatening hemorrhage and damage control surgery," continued Saunders. "In conjunction with the advances in battlefield trauma care, FDP allows the SOF medical provider to present a viable patient for damage control surgery and medical evacuation."
And yes, the use of FDP has saved lives.
To date, 16 patients in outlying areas have been treated with French FDP for life-threatening injuries, and 10 have survived to transfer of care, which is seen as a substantial number by many.
Recently, an Interservice Support Agreement was established between USSOCOM and USAMMDA to support and enable the expansion of French FDP to additional USSOCOM subordinate commands, including the Marines Special Operations Command, Air Force Special Operations Command, and Naval Special Warfare Command, for battlefield treatment of severe hemorrhage. Spurgers' primary task is to support and expand the use of French FDP to these other sites. Within the past year, he has briefed all groups on the protocol and has trained MARSOC, which will soon begin using this product in the field. Spurgers acknowledged that the other branches will follow after they are trained on the protocol.
But again, French FDP was intended only for interim use until a U.S.-based product is approved. Leading this charge is USAMMDA's Pharmaceutical Systems team, which has been involved with this effort since the very beginning, spearheaded by product manager Andy Atkinson. Working with Dr. Victor Macdonald, product manager and subject matter expert in blood products, Atkinson oversees research being conducted by Vascular Solutions Inc. in Minnesota, which has been "very proactive" in its efforts to progress this product. Working under a Cooperative Research and Development Agreement, Vascular Solutions is funding the manufacturing portion of this effort, while the Army, as the sponsor of this research, is funding the clinical trials necessary for advancement and approval of the U.S. FDP.
"The goal is to have this [U.S. FDP] product approved and readily available by 2020," said Atkinson. "You will be able to use this product up to point of injury on the battlefield; this is the key for its use."
Actually, the U.S.-based product will have many advantages over the current French FDP said Macdonald.
"The biggest advantage is that the U.S. FDP will be supplied in plastic bags, not in glass bottles [as is the French FDP], which means less weight, less bulk, and more rugged to avoid breakage," explained Macdonald. "Also, it will be U.S.-sourced plasma from a U.S. manufacturer."
"Another advantage of freeze-dried plasma is that it doesn't need to be frozen, which eliminates a power requirement for freezers," added Atkinson. "And no need to thaw it out ahead of time."
"The result is that the U.S. FDP will be logistically easier to handle, for both shipment and storage as well as during its use," said Macdonald.
While 2020 may seem a bit far off for approval of the U.S. product, the FDA's monitoring of the complex process of plasma collection, freeze drying, and packaging actually dictates this lengthy timeframe. Nevertheless, the FDA has remained very supportive of the Army's efforts.
"I think the FDA will continue to be cooperative, but it will remain stringent with regard to the validation of the manufacturing process," said Macdonald. "They [FDA] would like to see the U.S. product substituted for the French FDP."
But no one is cutting corners or bending rules, especially the teams of USAMMDA, as everyone involved understands the importance of producing a very safe and effective product, which eventually will be used in both military and civilian medical facilities, because of its shelf-life advantages over stored fresh frozen plasma.
As Macdonald asserted, "Although the FDA has said they have no jurisdiction over products that are sent overseas, our group still wants to maintain the same high U.S. standards regardless of this policy."
Macdonald continued, "I would like to say that Lt. Col. Andrew Cap from the U.S. Army Institute of Surgical Research played a pivotal role as an intermediary with the French military, authoring the clinical protocol for the expanded-access IND, and carrying out extensive laboratory testing of the product. It took a multi-institutional collaborative effort to make this happen."
With the task of managing the interim effort from start to finish, once the U.S. FDP product is approved and deployed, the FHP and DRAC offices will conclude their mission and move on to other critical projects.
"From the very beginning, this has been a stop-gap measure," said Miller. "I don't think anyone believed the French FDP would replace the need of developing an FDA-licensed freeze-dried product, as it didn't meet any of the FDA's requirements -- especially the glass bottles."
Although the effort has been extensive, the primary goal has always been the driving force: having a freeze-dried plasma product in place, at all times, to help save the lives of our Warfighters worldwide.
Regardless of the work involved, the USAMMDA teams resourcefully collaborate to make the seemingly impossible possible, doing whatever it takes to accomplish the given task -- and sometimes, this is a tall order to fill.
But in the words of Miller, they wouldn't have it any other way.
"Was it worth it? Did we save lives? If we saved even one life, then it was worth it," said Miller. "In a heartbeat, we would do it all again."
And fortunately for us, they do -- each and every day.