Back in September 2012, the US Food and Drug Administration (FDA) issued a little-noticed announcement in the Federal Register indicating that it was interested in starting a dialogue with the medical device industry to plan for the type of mass-casualty event-think a dirty bomb, mass explosion or some other chemical-based incident-that could leave thousands of patients, if not more, requiring medical care.
The meeting, part of the US Department of Health and Human Service's Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) was born out of a desire to strengthen the US National Stockpile (SNS) of medical products to protect US citizens against newer-generation threats.
One of the most pressing problems identified at the time was the issue of addressing the needs of burn victims. The Federal Register notice explained that a complete accounting of the entire US found just 1,850 burn unit beds in the entire US. Roughly half of those beds-spread across 126 different hospitals-are occupied at any one time, leaving around 900 available in the case of a mass casualty event.
That represents an enormous challenge for the existing medical establishment, as well as a critical opportunity for the medical device sector, FDA explained.
"In such an attack, stabilizing individuals with burns and concomitant injuries becomes an immediate priority," FDA wrote. "Medical care for burns in a mass casualty incident would require the ready availability of large quantities of medical countermeasures for resuscitation, wound management, pain relief, and nutritional- and airway/breathing support in the initial post-injury period."
In the aftermath of a terror attack involving particular chemical, for example, existing medical infrastructure could find itself quickly overwhelmed and unable to deal with the figurative crush of incoming patients. "The short supply of specialized burn experts and facilities may need to be considered one driver in regard to burn care product(s) design and development, enabling versatile use in the hands of non-specialists as well," noted FDA. Thus, having products that are relatively straightforward to administer without specialized training could mean the difference between life and death for many patients.
Medical Products Needed to Fill Critical Gap
"We like to say within the Center that the things you'll need first in the event of a dirty bomb or a chemical spill or a pandemic influenza are actually medical devices," Michelle McMurry-Heath, associate center director for science in FDA's Center for Devices and Radiological Health (CDRH), said according to a transcript of FDA's meeting on the subject.
"You'll need the diagnostic tools. You'll need the isolation equipment. You'll need the wound dressings. You'll need the respirators and the ventilators. You'll need all of the things that actually are overseen by the Center for Devices," continued McMurry-Heath. "And so, we're very happy that you're here today to have a conversation with us about how best to approach this very important area."
"We all have skin in the game here," added Suzanne Schwartz, acting director for medical countermeasures in CDRH. Schwartz recalled being "off-guard, stunned and unprepared" when she and her colleagues at the Weill Cornell Medical Center in New York were among the first to respond to patients afflicted by the attacks on the World Trade Center in 2001.
"But those raw feelings of vulnerability, those images, striking images of destruction, of loss, of despair and shock, they never quite leave us as they become locked in our collective consciousness, especially as they invoke memories of what it was like to be there in the moment," said Schwartz, "And in some ways that's a good thing, because they impel us to make that promise and maintain that commitment to never allow ourselves to be in this position ever again."
To that end, she added, the agency was looking for ideas that it can act upon.
Imagining the Unimaginable
Other parts of the talk speak to the potential physical environments some victims might be treated in. Speaker Rick Jaffe of the Medical Countermeasure Strategy Requirements Group of PHEMCE, noted that a 10 kiloton nuclear blast wouldn't have a response measured in minutes, but in days. Even smaller nuclear events, such as those from a dirty bomb-perhaps ironic in that medical devices have been cited as being a source of the nuclear material for such devices-could make responding to the event tricky as the result of the radiation fallout.
The key to responding, said Radm Clare Helminiak, assistant secretary for preparedness and response (ASPR) at the US Department of Health and Human Services, is that all sectors-federal, state, local and private-will have to be leveraged to ensure an appropriate response in the case of a disaster. "As you know, all disasters are local," Helminiak observed. "So you all are going to own a disaster until help arrives."
In that vacuum, the standards of medical care are likely to experience a radically different paradigm, Helminiak explained. "You're not talking about cosmetic repair and restoring people to the fullest life possible. You're talking about saving lives, and you're talking about preserving some level of functionality. So it's not the normal paradigm and the very excellent medical care that we provide burn patients in America."
"We've learned that burn wounds do not require immediate specialized intervention," said Ron Manning, also of DHHS's ASPR. "In other words, you can stabilize the patient and you can buy some time. And that's important if you're thinking about a response where the system is overwhelmed."
The (Challenging) Market Opportunity for Devices
Enter: an opportunity for medical devices, albeit a challenging one.
Manning observed that, as with pharmaceutical products developed under the Animal Rule pathway, products for rare, small-use markets need to be given incentives to develop a particular treatment, especially given the costs and risks to development. "If there isn't sufficient use, products will flounder or investment capital will not be there at the right time in the right amount," Manning said.
One of the other problems identified by Manning is the cost of certain treatments, which have hindered future generations of wound and burn care products. "A synthetic skin substitute is a whole lot more expensive than an autograft or cadaver skin or pig skin," he observed. "So how can we make these products more cost-competitive so they can enter into the marketplace?" He added that the cost of a given treatment, though high, can actually have alternate benefits that could bring the total cost of treatment down, resulting in a potentially better clinical outcome.
Those clinical outcomes are vastly different depending on the scenario being dealt with. For example, a skin graft might be cheaper, but in a human capital resource-poor environment after a disaster, something that can be easily administered-though more expensive-could save lives by reducing wait times and stabilizing patients.
The obvious problem: Disasters are, by definition, not an everyday occurrence, and getting a market-rate return on investment can be extremely difficult for companies under those circumstances even if their product fits a potential need.
"It's largely the lowered return on investment that actually causes product stagnation and actually drives down our national capacity for preparedness, which is what [the government is] really worried about," Narayan Iyer, an official with the Biomedical Advanced Research and Development Authority (BARDA), said.
"Clearly, we have about 300, 400 burn surgeons [nationwide]." Iyer added. "Someone said that you're going to need 1,500. You're not going to meet that. So we clearly need products that are actually going to be useful by other than burn surgeons."
Clearing Regulatory Hurdles and Using New Approaches
And getting those next-generation, novel products to market means getting over regulatory hurdles as well, conference participants observed. Many, if not most, products to treat burn victims would be cleared through either a premarket approval (PMA) or biologics licensing application (BLA) process. CDRH Reviewer Charles Durfor noted that for many products, the review process would be an opportunity to answer some questions beyond the product's indications, such as its shelf life and stability.
But Durfor also raised an interesting prospect: having a compiled list of possible off-label uses. The morning of 9/11, Durfor said, he was "actually going through files looking for information for off-label use."
"One change that I think would be particularly helpful is when we get applications such as a BLA, such as an [New Drug Application] NDA, such as a PMA, is to have a table of contents that lists these other studies that may not be directly related to its clinical use in the normal population," Durfor added. He said he would like to see such information in a "single place" that is readily accessible in the case of an emergency.
A number of other difficulties also surround the treatment of-and thus the testing of a product on-patients with burns. Which antimicrobial products are administered to a patient, for example, might affect its efficacy.
On the biologics side, Steven Oh, team leader of Cellular, Tissue and Gene Therapy division of the Center for Biologics Evaluation and Research (CBER), said drug makers have some leeway in getting products approved.
Being Flexible With Regulatory Approaches
"For some of the other testing that you would still need to carry out, there is no specific method that's specified in the regulation, which means that it is up to the product developer to come up with and justify as to why you think this is the best way to characterize that product," Oh said. "And it is that flexibility that we have from our office point of view as well."
"Use your best scientific judgment and make sure that you have scientific reason behind why you're doing this in this way at this time point and then come up with a set of characterization methods that you would want to discuss with FDA," he added. "And our office would be happy to discuss these on a product case by case."
As these products move forward, other regulatory issues are likely to emerge, observed other workshop participants. Though many therapies are developed by larger, more established companies, academic and research centers are also working on products in the field. These institutions have "relatively little experience dealing with FDA and FDA-regulated products," explained Dave Shoemaker, a participant. "From my perspective, it's very important to get them connected with the companies early on to help provide that regulatory strategy and knowledge base to keep moving these products along."
FDA reviewers also said they have the ability to issue emergency-use authorizations to approve products in the case of a "very dire public health need," but added that "At all times, we are looking at the need against the science, the data that supports [a company's] intended use of the product in the regulatory framework."
These emergency use grants could be used to approve a new, experimental product in a short amount of time, or simply to allow an already-approved product to be legally marketed for new indications in the case of an emergency.
What's clear from much of the meeting, though, is that individual products will require individual approaches. Numerous FDA reviewers spoke to the importance of pre-submission meetings, which usually occur after the submission of an investigational new drug (IND) application or investigational device exemption (IDE).
"My advice when we talk about this, and you've said it, is to work-and it's something we did, is work closely with FDA," said Judith O'Grady, RAC, of the firm Integra LifeSciences. O'Grady said her firm had already brought a product through FDA's regulatory processes-a 13-year process from start to finish.
"I cannot stress [that] enough," she added.