The Armed Forces Institute of Regenerative Medicine (AFIRM) is yet another major medical outgrowth of the decade-long war in Southwest Asia. It was created by the U.S. Army Medical Research & Materiel Command (MRMC) in 2007 to develop and oversee a network of academic research teams working on advanced treatment options for severely wounded warfighters.
AFIRM is considered a “virtual organization,” comprising multiple universities working in conjunction with the Army Institute of Surgical Research (ISR) under a five-year cooperative agreement focused primarily on wound repair and organ/tissue regeneration. In addition to MRMC, the institute receives funding and support from the Office of Naval Research, the Office of the Surgeon General of the Air Force, the National Institutes of Health (NIH), the Department of Veterans Affairs (VA) and Department of Defense (DoD) Health Affairs, as well as local public and private matching funds.
In response to a January 2007 Request for Information issued by MRMC, two consortia, each composed of 15 universities, were awarded $42.5 million apiece for a five-year, multidiscipline effort to develop new products, technologies, and techniques for clinical trial and, eventually, use in treating wounded warriors. In large part, the more than 300 scientists in the consortia are seeking answers to medical treatment gaps defined by the Army Medical Department (AMEDD).
The two groups – one headed by Rutgers University and the Cleveland Clinic, the other by Wake Forest University and the McGowan Institute in Pittsburgh – while working under separate awards, quickly began a close collaboration with each other and ISR. They also have raised more than $200 million in additional funds, distributed among their members according to peer-reviewed work plans designed around AFIRM’s objectives.
AFIRM Director Terry Irgens is a retired Navy pharmacist, hospital executive officer, and medical logistician with an additional background in medical records IT and the U.S. Food and Drug Administration (FDA) licensing process. He and his staff of six – drawn from ISR and the two consortia – manage the overall process, provide the universities and scientists with updates on technology changes, and advise them on the FDA regulatory process.
“When this began, we had a lot of wounded warriors coming back with severe disfigurations, missing limbs, and other injuries that were unusual because, in the past, the survival rate for those was not as great as today,” Irgens explained. “A lot of research going on in regenerative medicine was ‘way out there,’ so to speak, but up and coming. DoD held some conferences on the topic and experts explained what was being done in growing organs, tissue growth, different scaffolds for making ears and such.
“Some military medical personnel at the time felt it would be helpful to wounded warriors to help move that research forward. So they put out a project announcement in 2007, focused on five areas: burns, scarless wound treatment, limb and digit salvage, compartment syndrome repair, and wounds to the face, with burns being the most critical item at the time. They received seven responses from academic consortia. At the same time, President [George W.] Bush got interested in this technology and was able to double the funding, so awards were given to two consortia instead of only one, each of which covered all five focus areas.”
In the past two or three years, the number of severe burn cases has declined, he added, and, while still a major priority, loss of limbs has become the primary focus. But that initial priority is why so many of the products currently in trials relate to burns.
“The primary driver was the number of casualties returning, which was a good thing in terms of a high battlefield survival rate, but they were coming back with catastrophic injuries that required new technologies and treatments,” Irgens said. “Some, such as stem cells, have been around a long time, but have not been researched as fully and quickly as possible.
“We use adult, not embryonic, stem cells, which are present in most areas of the body. The idea was to propel some of those technologies forward, such as putting stem cells into damaged areas of the face, which can make the wounded look better [an important psychological component of treatment] and facilitate healing.”
Primary advances in battlefield support during the current war in Southwest Asia, from personal tourniquets to artificial blood to rapid transport of the wounded, have had a major impact on combat casualties. During World War II, Irgens noted, the survival versus casualty rate was about 70 percent, compared to 90 to 95 percent in Southwest Asia as the past decade of combat has evolved. Much of that is due to greatly improved personal and vehicle armor, but also better and earlier treatment during the first hour– the “golden hour” – after being wounded.
The primary cause of injuries in the current conflict has been the IED – improvised explosive device. Improved armor and battlefield care have kept alive wounded warfighters who would not have survived any previous war, but also led to a substantial increase in severe wounds to the face and limbs. The pressure on military medicine then became a way to improve the survivors’ quality of life.
Lt. Col. Michael R. Davis (USAF), ISR’s chief-Reconstructive Surgery & Regenerative Medicine, said AFIRM is playing a critical role in advancing both surgical and non-surgical approaches to the most severe combat wounds coming out of Iraq and Afghanistan.
“There has been a large amount of support from DoD through agencies such as AFIRM, which has allowed a synergistic environment between academic institutions and the military to really very rapidly develop these technologies and get them into the clinical arena and to the soldiers,” he said.
“Typically there is a bit of a competitive atmosphere and parallel research in the academic community, but AFIRM has set up an environment of collaboration so things can advance much further and faster. It all comes together to really help the injured soldier and the people involved are very motivated.”
Having so many universities and scientists working in close collaboration also led to a significant change in the status of and expectations for AFIRM and its initial five-year effort.
“AFIRM began as part of CRMRP [Clinical & Rehabilitative Medicine Research Program] because it clearly was a science and technology [S&T] effort and they did not anticipate clinical trials, even after five years. But we saw we were getting closer to advanced development, so last year, when I came on board, it was moved from CRMRP to USAMMDA [U.S. Army Medical Materiel Development Activity] because we needed more expertise in regulatory requirements for our clinical trials,” Irgens said. “We still work with CRMRP because they provide the basic funding for the grant.
“By working together, the two consortia have been able to propel research much faster than anticipated. The original goal was to have one product in a patient after five years. That was achieved after the second year for burn treatment. Now we have 11 clinical trials ongoing, so, unlike a lot of contracts that tend to fall behind, we’re actually moving faster than anticipated, which is a good thing for the wounded warrior.”
The current agreement ends in September 2014, but the government is expected to put out a request a year or two earlier for a follow-on program – open not only to the two current groups but to any others that can demonstrate the required capabilities. With tighter budgets and funding, Irgens said AFIRM II may only involve one consortium, but the request will leave it open to “one or more.” AFIRM II is expected to continue work on the same five focus areas, although Irgens said one or two additional areas may be added.
Just as AFIRM, although housed within and largely funded by the Army, is a multiservice, multi-university effort, it also involves a broad range of other federal agencies. Both the VA and NIH provide funding and are on the science advisory board, as are other service and defense health programs.
“The VA involvement is critical because, eventually, all wounded warriors will wind up with them. In addition, we’re not designing therapies unique to the military, but treatments that can be used by the civilian community, as well,” Irgens noted. “What we’re funding is what they call the ‘Valley of Death,’ where a lot of projects get a good start under S&T, but then funding becomes scarce once they get into animal studies and such. So that is where we are helping in the process.
“The two consortia combined have 72 projects in different levels of development, leading up to trials. Overall, the goal is to make sure the technology or therapy is safe for the patients, so strict procedures are enforced. You can’t just say something works; you have to explain how and why it works to meet FDA requirements.”
The basic grants were supplemented by about $20 million from Defense Health, $60 million from states (supporting their local universities in the consortia), and $109 million from DARPA, NIH, the National Science Foundation, and philanthropy, along with annual congressional plus-ups (aka earmarks).
“Officially, there are no more earmarks, but they have been replaced by congressional special interest funding, not to any specific university but to AFIRM, which we are using for clinical trials,” he added. “The VA also has provided funding and is on our board of directors and our IPTs [Integrated Product Teams]. So we work closely with the VA and hope to continue doing so in the future. They have their own projects, but we have a very collegial collaboration with those, as well.”
The AFIRM consortia have five projects at the FDA Phase 1 level, which is a safety study using a small group of patients and a primary goal of proving the treatment is safe; another five at Phase 2, a bigger study to determine levels of dosing and results; and one in Phase 3, an extended study with the right number of patients to pass FDA regulatory hurdles. Another five products are expected to enter clinical trials in the next 12 months.
The Phase 3 project is called ReCell Autologous Spray On Skin, a process where a small skin sample, about the size of a postage stamp, is taken from a burn patient; doctors then process the cells and use a special spray device to cover a burn area up to 80 times the size of the biopsy with the patient’s own cells, eliminating the risk of rejection while new cells grow. A Wake Forest team product, ReCell is being sponsored through the FDA trials by Avita Medical, using a new spray gun developed by the McGowan Institute.
“Scarring is an obvious problem and if you can reduce scarring, it is better. In Phase 2, a polymeric device from Neodyne Biosciences is put over the scar, applying pressure and pulling the skin together. It has been shown to reduce the size and depth of the scar,” Irgens added. “Another program is looking at using two layers of skin – currently cadaver skin – on burn patients, which means you don’t have to rely on the patient’s own skin and cells.
“Another approach is adipose fat transfer, where fat deposits are taken from the patient, processed for stem cells, put into syringes, and then injected around the face where surgery or injury has caused problems. It is longer lasting than other procedures and, although they haven’t begun this yet, they are looking at using it on patients who do not have a good fit for their prosthesis, using it to build up the tissue to get a better fit. So it is functional as well as cosmetic. A lot of that work is being done at the University of Pittsburgh.”
A number of enabling technologies are employed in the various AFIRM projects, although Irgens cites scaffolds as among the most successful. Scaffolds essentially are biodegradable skeletons the shape and size of the body part to be replaced. When the patient’s own cells, drawn from the bladder, for example, are “seeded” onto the scaffold, new cells grow around it to form a new bladder. Scaffolds also can be used where there is a major gap in nerve or vascular conduits.
“If we can unlock immunotolerance, you can imagine the applicability of composite tissue transplantation for reconstruction. To adequately reconstruct a defect, you really need like tissues, so to be able to transplant tissues whose primary function is to revitalize that defect will always result in a better outcome for the patient,” Davis explained.
Although AFIRM and numerous other military medical programs were created to deal with casualties from the current war, Irgens expects the aggressive new emphasis on advancing medical capabilities to “reset” even the most severely wounded service members will continue after U.S. forces have left Iraq and Afghanistan. Even so, in a time of ever-tighter budgets, he admited, “it’s hard to know.”
“We will still have a lot of wounded warriors who will potentially benefit from these technologies long after any specific war ends. Catastrophic injuries, such as the loss of an arm, will still exist, as will the work we are doing on hand transplants and finding ways to enable patients not to require so many suppressant drugs, which lower the body’s immune system,” he predicted.
“That also is true with regeneration of ears and such. It may not be at the level we currently are funded, but we will continue to move through the regulatory path because there also is a civilian need, such as firefighters and burn treatment. If we get a couple of licensed products from this process, that definitely will propel additional funding.”
ReCell is closest to being licensed, Irgens added, and when those clinical trials are completed in early 2012 and a license application made to the FDA, “We feel it has a good chance to be approved, so we expect it to be the first AFIRM-sponsored product to be licensed. A close second would be the Neodyne device, which has a different regulatory path, going for FDA approval, as opposed to licensing.
“By the time they get into clinical trials, they have a commercial sponsor to carry the product to approval, so it really wouldn’t be dependent on AFIRM at that point,” he said of the process from initial study to FDA approval or licensing. “Those still in early S&T will have to fight for funding, through NIH or as part of AFIRM II, depending on the successful winner of that competition. We want to keep our momentum going, but we are doing better so far than expected.”
That momentum and anticipated future successes also make AFIRM a model on which future research consortia may be based.
“A lot of consortia have been tried in other settings, such as NIH, but have not worked as well as they have with AFIRM, where the military focus is more of an urgent and focused need compared to other efforts. Wake Forest and Rutgers, for example, are dedicated to doing what is right for the patient, which is one reason they work so well together,” Irgens noted.
“NIH folks have said we need to advertise the success of the AFIRM consortia; there already are other consortia, such as orthopedic, based on the AFIRM approach and there are others looking into doing the same – including some that currently are part of AFIRM, such as face and hand transplants. Need will drive the requirement, but AFIRM definitely has been a successful program model.”
Davis also believes the future holds great promise from medical research being done by the military, especially efforts such as AFIRM.
“Research into regenerating blood vessels, facial tissue, cartilage, bone, muscle, and so on are under way, both within AFIRM and ISR, but those are in their infancy. We’re not to the point where we can, with any facility, reconstruct a hand. But the future holds great promise with stem cells and advancements in scaffolds,” he said.
“Cloning falls under the larger heading of tissue engineering, which also is a focus of AFIRM and at ISR. But something like ear reconstruction and providing a scaffold for cloning functionalized tissue is definitely an option to be considered.”
For Irgens, the pursuit of technologies and techniques previously – in some cases, still – considered “science fiction” is or well may be a part of both current and future AFIRM projects.
“If you take the term ‘regenerative medicine’ in a broad base, beyond what we do in AFIRM, they are regenerating bladders, even heart muscles. Those are not part of AFIRM, but it is a field that has really been growing,” he concluded. “Eventually, it would be nice to regenerate an arm, the way salamanders do, but that is not something we are touting today.”
This article first appeared in The Year in Veterans Affairs & Military Medicine: 2011-2012 Edition.